Effectiveness of varenicline as an aid to smoking ...

Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2011.557718

Vol. 27, No. 4, 2011, 769–775

Article ST-0046.R1/557718 All rights reserved: reproduction in whole or part not permitted

Hedwig Boudrez

Heart Centre, University Hospital Ghent, Ghent, Belgium

Christina Gratziou

Evgenidio Hospital, Medical School, University of Athens, Athens, Greece

Abstract

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Curr Med Res Opin Downloaded from informahealthcare.com by UG - VIB on 05/30/11 For personal use only.

Original article Effectiveness of varenicline as an aid to smoking cessation: results of an inter-European observational study

Background: Varenicline tartrate, a selective partial agonist of the a4 2 nicotinic receptor, has been shown to be an effective smoking cessation aid with an acceptable safety profile in a number of randomized, controlled trials. The aim of the CHOICES (Champix Observational Investigation in the Cessation of Smoking) study was to investigate the effectiveness and safety of varenicline in real-world clinical practice.

Michael Messig

Pfizer Inc, New York, NY, USA

Michael Metcalfe Pfizer Ltd, Tadworth, UK

Address for correspondence: Prof Dr Hedwig Boudrez, Heart Centre, University Hospital Ghent, De Pintelaan 185, Ghent 9000, Belgium. Tel.: þ32 9 332 33 32; Fax: þ32 9 332 33 87; [email protected] Key words: Observational study – Smoking cessation – Varenicline

Accepted: 10 January 2011; published online: 4 February 2011 Citation: Curr Med Res Opin 2011; 27:769–75

Methods: The CHOICES study was a 12-week, prospective, observational, non-comparative study of varenicline conducted in four European countries (Belgium, Greece, Hungary, and Slovenia) between November 21, 2007 and August 3, 2009. Participants were prescribed varenicline according to the recommendations on the European Summary of Product Characteristics (SmPC). Smoking abstinence rates in the 7 days between week 11 and 12 were determined based on verbal reporting using a nicotine use inventory. The safety profile of varenicline was also assessed. Results: Of 566 participants enrolled in this study, 551 received varenicline and were evaluated for effectiveness and safety. At baseline, the overall study population had a mean age of 45.5 years; a mean history of smoking of 27.0 years; and a mean score on the Fagerstro¨m Test of Nicotine Dependence (FTND) of 6.1. Overall, 64.6% (95% CI 60.1, 68.3) of participants successfully quit smoking by the end of the treatment phase at week 12. The most frequent treatment-emergent (all causality) adverse events were nausea (8.9%), insomnia (2.9%), and sleep disorder (2.2%) of mostly mild or moderate intensity. Discontinuations from the study due to treatment-related adverse events occurred in 3.4% of participants. Limitations: Abstinence rates were not validated by carbon monoxide measurements, as this is not a practice uniformly used in European countries. Conclusions: The CHOICES study shows that in a real-world clinical practice setting outside a clinical trial environment, varenicline is an effective smoking cessation aid with an acceptable safety profile. ClinicalTrials.gov identifier: NCT00669240

Introduction The worldwide burden of tobacco use is high and is responsible for an increasing but avoidable annual mortality rate1. Stopping smoking is beneficial both before ! 2011 Informa UK Ltd www.cmrojournal.com

Observational European varenicline study Boudrez et al.

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the onset of related disease and after. Therefore, prevention and smoking cessation remain important goals in public health policy. Although up to 70% of smokers express a desire to quit2,3, only 41% had engaged in a real quit attempt in the previous year3. Moreover, most untreated smokers relapse within the first 8 days after quitting4 and success rates of unassisted attempts after 1 year remain very low at 4–7%5. Nicotine dependency is considered a chronic condition, similar to other substance use disorders, requiring specific and in some cases long-term treatment6. Nicotine acts as an agonist of the nicotinic acetylcholine receptors (nAChRs) in the central nervous system, activating the dopaminergic rewarding pathway and contributing to positive reinforcement and dependence. Chronic use of tobacco results in the development of tolerance and withdrawal symptoms. Several drugs, especially nicotine replacement therapy (NRT) and bupropion, have been developed in order to tackle the pharmacological dependency created by the use of tobacco. Varenicline is the most recent drug, created for pharmacological assistance of smoking cessation. It acts as a selective partial agonist of the a4 2 nicotinic receptor. Varenicline helps to relieve craving and withdrawal symptoms, and blocks the rewarding effects of nicotine. Several randomized controlled trials (RCTs) have evaluated the efficacy and safety of varenicline7–14. Varenicline was shown to yield elevated abstinence rates, compared with the placebo and bupropion control groups, presenting an acceptable safety profile. Nausea and insomnia were the most frequently reported adverse events (AEs) (nausea, 30%; insomnia, 14%); however, these were experienced at modest intensity and did not lead to premature discontinuation of treatment10,15. Recently, the efficacy and safety of varenicline were demonstrated in patients with cardiovascular disease7 and in patients with chronic obstructive pulmonary disease (COPD)16. A recent Cochrane meta-analysis estimated the odds ratio of quitting using varenicline to be between two- and three-fold compared with pharmacologically unassisted attempts17. The latter review also emphasized the need for community-based trials of varenicline17. Observational studies – which are designed to evaluate the clinical effectiveness of a treatment in a real-world clinical surrounding – are considered to be of lesser value in the hierarchy of study designs than RCTs18. However, observational studies can also be considered as useful and complementary to RCTs19,20. The inclusion of a greater heterogeneity of participants in observational studies, including those with characteristics – for example, the presence of comorbidities– that are excluded in RCTs, is one of the most significant advantages of real-world, population-based studies21. Their results may add value to the external validity of RCTs by expanding the settings to a more representative clinical population20. The results of observational studies and RCTs mostly show a high 770


correlation, although the magnitude of the treatment effects may vary due to differences in the stringency of the inclusion criteria20,22. In addition to a growing number of RCTs, several observational real-world studies have been reported for varenicline. Encouraging abstinence rates were observed in highly dependent smokers receiving varenicline in two smoking cessation clinics in Spain, showing AE rates that were comparable with those seen in RCTs of varenicline23,24. A non-randomized cohort study of varenicline prescriptions issued by general practitioners in the United Kingdom described the post-marketing safety profile (specifically for suicidal behaviors and new-onset depression) in a clinical setting25. Finally, a study in a real-world setting found that tolerance of varenicline and treatment compliance were enhanced by counseling26. The CHOICES (CHampix Observational Investigation in the CEssation of Smoking) study investigated smoking abstinence rates and the safety profile of varenicline treatment in a real-world practice setting.

Methods Study population and design The CHOICES study was a 12-week, prospective, observational, non-comparative trial conducted in four European countries (Belgium, Greece, Hungary, and Slovenia) between November 21, 2007 and August 3, 2009. Adult smokers were eligible for inclusion in the study if, in the clinical judgment of their supervising physician, they were suitable candidates for treatment with varenicline for smoking cessation. Participants were prescribed varenicline in accordance with the recommendations on the European Summary of Product Characteristics (SmPC)27. The smoker determined a quit date and was provided with study medication to commence treatment up to 2 weeks prior to the quit date. The cost of the varenicline prescriptions was covered according to local reimbursement policy. A schematic overview of the design of the CHOICES study is shown in Figure 1.

Prior and concomitant medications and comorbidities There were no restrictions on prior and concomitant medications or comorbidities apart from the usual prescribing information in the SmPC27.

Fagerstro¨m Test of Nicotine Dependence Nicotine dependence was assessed at enrolment using the Fagerstro¨m Test of Nicotine Dependence (FTND), which consists of six questions. A total score was calculated as a www.cmrojournal.com ! 2011 Informa UK Ltd


Enrollment

Prior to Week 0

Start treatment

Week 0

QUIT smoking

Efficacy

Week 11

Week 1- 2

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Stop treatment

Week 12

Figure 1. Study design.

sum of these six questions, with lower scores indicating lower dependence on nicotine: 0–2, very low dependence; 3–4, low dependence; 5, medium dependence; 6–7, high dependence; and 8–10, very high dependence.


Clinical evaluations The use of nicotine was recorded based on verbal reporting using a nicotine use inventory (NUI) to determine the smoking status of the participant. The NUI consisted of the following two questions: ‘Has the subject smoked any cigarettes (even a puff) in the last 7 days?’ and ‘Has the subject used any other tobacco products (e.g., pipe, cigars, snuff, chewing tobacco) in the last 7 days?’ Continuous abstinence was determined at week 12 using NUI assessment, for the 7-day period between weeks 11 and 12. NUI assessments were also carried out at interim visits any time between weeks 3 and 11. Interim visits took place only if they were part of normal practice for smoking cessation attempts. Carbon monoxide (CO) levels were measured and recorded to confirm abstinence in some, but not all, participating countries where this was standard practice.

percentages for categorical variables and as means and standard deviations for continuous variables. Exact Clopper–Pearson 95% confidence limits for the abstinence rates were determined based on the binomial distribution.

Results Baseline demographics Overall, 566 participants were enrolled in the study. Of these, 551 received study medication and were evaluated for effectiveness and safety. The mean age for the overall population was 45.5 years, 53.5% were men, and 97.1% were white. Mean smoking history was 27.0 years; the average number of cigarettes smoked per day was 25.3; mean score on the FTND was 6.1, and the mean number of previous serious quit attempts was 1.6 (Table 1).

Use of behavioral support Overall, a third of participants (169/551 [33.5%]) received smoking cessation behavioral support during the study (138/226 [71.1%] in Belgium; 20/196 [10.8%] in Greece; 11/107 [10.3%] in Hungary; and 0/22 [0%] in Slovenia).

Behavioral support A smoking cessation behavioral support program was available to all participants during the study according to routine local practice, to complement the treatment with varenicline. In addition, a manufacturer-supported web- or paper-based behavioral support program was available in participating countries with the exception of Greece. This support program was available to all varenicline patients in those countries where the program was active.

Safety evaluations AEs were reported descriptively using Medical Dictionary for Regulatory Activities (MedDRA) coding. Safety data were collected and assessed using standard methods from smoking cessation trials.

Prior and concomitant medications and comorbidities The most common medications prior to the start of the study were acetylsalicylic acid (31/551 [5.6%]), seretide mite (31/551 [5.6%]), atorvastatin (25/551 [4.5%]), and tiotropium bromide (25/551 [4.5%]). The most common concomitant medications during the study were seretide mite (34/551 [6.2%]), acetylsalicylic acid (31/551 [5.6%]), and tiotropium bromide (26/551 [4.7%]). The most common prior or concomitant comorbidities relevant to smoking were elevated cholesterol (20.7%), hypertension (20.0%), and COPD (18.2%). Furthermore, 9.4% of participants reported past or present depression, while 3.3% had experienced other psychiatric disorders.

Statistical analysis The analysis included all enrolled participants who had received at least one dose of study medication. Descriptive summaries were provided as counts and ! 2011 Informa UK Ltd www.cmrojournal.com

Compliance and duration of treatment exposure Overall, 149 (27.0%) participants discontinued from the study (Belgium: 36.7%; Greece: 20.4%; Hungary: 16.8%; Observational European varenicline study Boudrez et al.

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Age, years mean (range) p50.001 between countries Men, n (%) p ¼ 0.279 between countries Race, n (%) White Asian Other Unspecified p ¼ 0.333 between countries BMI, kg/m2 mean (SD) p50.001 between countries Total number of years smoked mean (SD) p50.001 between countries Average number of cigarettes per day mean (SD) p50.001 between countries FTND Score mean (SD) p ¼ 0.003 between countries Number of serious quit attempts mean (SD) p ¼ 0.360 between countries

Belgium (n ¼ 226)

Greece (n ¼ 196)

Hungary (n ¼ 107)

Slovenia (n ¼ 22)

Total (n ¼ 551)

46.1 (20–76)

42.6 (19–67)

50.6 (22–75)

47.0 (21–75)

45.8 (19–76)

127 (56.2)

107 (54.6)

53 (49.5)

8 (36.4)

295 (53.5)

216 (95.6) 1 (0.4) 5 (2.2) 4 (1.8)

191 (97.4) 0 (0.0) 0 (0.0) 5 (2.6)

106 (99.1) 0 (0.0) 0 (0.0) 1 (0.9)

22 (100.0) 0 (0.0) 0 (0.0) 0 (0.0)

535 (97.1) 1 (0.2) 5 (0.9) 10 (1.8)

24.8 (4.8)

26.3 (4.9)

27.6 (5.6)

23.8 (3.3)

25.9 (5.0)

28.3 (12.9)

23.4 (9.9)

30.9 (11.5)

27.5 (9.4)

27.0 (11.8)

22.2 (8.4)

29.9 (14.3)

23.9 (8.2)

24.0 (9.6)

25.3 (11.4)

6.0 (2.2)

6.6 (2.3)

5.9 (1.8)

5.3 (2.6)

6.1 (2.2)

1.7 (0.5)

1.6 (0.5)

1.6 (0.5)

1.5 (0.5)

1.6 (0.5)

BMI, body mass index; FTND, Fagerstro¨m Test of Nicotine Dependence.

All participants 100 Success rate for smoking cessation (%)


Table 1. Baseline demographics by country and for overall population.

Total

90 80 70

64.6

70.4 61.1

Belgium 64.5

60

Greece 50.0

50

Hungary Slovenia

40 30 20 10 0

356/551

138/226

138/196

69/107

11/22

Figure 2. Success rates for smoking cessation in the 7-day period between weeks 11 and 12, all populations and by country. All participants, all enrolled participants who had received at least one dose of study medication (either morning, evening, or both of the planned twice-daily doses).

Slovenia: 36.4%). The median duration of treatment was 83.0 days, with approximately half of all participants (280/551 [50.8%]) taking varenicline for 61–90 days.

For the interim visits between weeks 3 and 11, the number of participants was low and decreased over time and, consequently, the results are inconclusive and not presented here.

Clinical evaluations By the end of the treatment phase, in the 7-day period between weeks 11 and 12, 356/551 (64.6% [95% confidence interval (CI) 60.1, 68.3]) of participants had been abstinent: 138/226 (61.1% [95% CI 54.1, 67.2]) in Belgium; 138/196 (70.4% [95% CI 63.5, 76.7]) in Greece; 69/107 (64.5% [95% CI 54.1, 72.9]) in Hungary; and 11/22 (50.0% [95% CI 26.8, 69.4]) in Slovenia (Figure 2). Of these, only a small proportion of participants had used NRT in the 7-day period prior to week 12 (26/551 [5.3%] for the total population). 772


Safety evaluations Nineteen (3.4%) participants discontinued due to treatment-related AEs. The most frequent treatment-emergent AEs for the total population were nausea (8.9%), insomnia (2.9%), and sleep disorders (2.2%) (Table 2). The most common treatment-emergent psychiatric disorders were insomnia (2.9%), sleep disorder (2.2%), and abnormal dreams (1.8%) (Table 3). Seven patients had serious AEs and one patient died (unrelated to study drug; cause of death: metastases to the central nervous system). www.cmrojournal.com ! 2011 Informa UK Ltd


Table 2. Incidence of treatment-emergent adverse events (all causality) occurring in 1% of all participants. Total population (N ¼ 551)


Nausea Insomnia Sleep disorder Abnormal dreams Abdominal pain, upper Fatigue Gastritis

Total n (%)

Mild n (%)

Moderate n (%)

Severe n (%)

49 (8.9) 16 (2.9) 12 (2.2) 10 (1.8) 9 (1.6) 7 (1.3) 6 (1.1)

30 (5.4) 11 (2.0) 6 (1.1) 7 (1.3) 4 (0.7) 1 (0.2) 4 (0.7)

15 (2.7) 4 (0.7) 4 (0.7) 3 (0.5) 2 (0.4) 5 (0.9) 1 (0.2)

4 (0.7) 1 (0.2) 2 (0.4) 0 (0.0) 3 (0.5) 1 (0.2) 1 (0.2)

Table 3. Incidence of treatment-emergent psychiatric adverse events (all causality). Total population (N ¼ 551)

Insomnia Sleep disorder Abnormal dreams Nervousness Depressed mood Nightmares Apathy Generalized anxiety disorder Hallucination Impulsive behavior Mental disorder Stress

Total n (%)

Mild n (%)

Moderate n (%)

Severe n (%)

16 (2.9) 12 (2.2) 10 (1.8) 3 (0.5) 2 (0.4) 2 (0.4) 1 (0.2) 1 (0.2)

11 (2.0) 6 (1.1) 7 (1.3) 2 (0.4) 1 (0.2) 1 (0.2) 0 (0.0) 0 (0.0)

4 (0.7) 4 (0.7) 3 (0.5) 1 (0.2) 0 (0.0) 1 (0.2 1 (0.2) 1 (0.2)

1 (0.2) 2 (0.4) 0 (0.0) 0 (0.0) 1 (0.2) 0 (0.0) 0 (0.0) 0 (0.0)

1 (0.2) 1 (0.2) 1 (0.2) 1 (0.2)

0 (0.0) 1 (0.2) 0 (0.0) 1 (0.2)

1 (0.2) 0 (0.0) 0(0.0) 0 (0.0)

0 (0.0) 0 (0.0) 1 (0.2) 0 (0.0)

Discussion The CHOICES trial was an observational study designed to evaluate the effectiveness and safety of varenicline in a real-world smoking cessation practice setting in four European countries: Belgium, Greece, Slovenia, and Hungry, in accordance with the recommendations on the European SmPC. No special inclusion or exclusion criteria were specified. At the end of treatment (12 weeks), an overall abstinence rate of 64.6% was observed, showing highly comparable results between three of the four participating countries. These results exceed the (continuous) abstinence data that were observed after 12 weeks in pre-registration RCTs: 44%15, 43.9%10, 40.8%13, and 49.4%28. This difference may be explained by several reasons. First, abstinence in our observational study was defined as pointprevalence abstinence (no smoking in the 7 days prior to assessment). Continuous abstinence represents a more rigorous evaluation of smoking abstinence than point prevalence abstinence. However, the abstinence rate in the CHOICES trial exceeds even the point prevalence ! 2011 Informa UK Ltd www.cmrojournal.com

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abstinence data in the RCTs: 50%15, 50.310, and 60%28. Oncken found comparable point prevalence abstinence data of 60%28. Tonstad (maintenance trial) observed a 7-day point prevalence abstinence at week 12 of 64.1%; these are probably the most comparable data, as the trial involved open-label treatment29. Theoretically, the lack of CO-confirmed abstinence in the CHOICES study participants can be hypothesized to account for some overestimation of true abstinence by misclassification of non-responders on the basis of unreliable verbal reports of smoking state. The reliability of scientific data on self-reported smoking state is a matter of some debate: a number of studies have demonstrated an underestimation of smoking status, based on self report in well-defined subgroups of smokers, such as pregnant women30 and patients with malignant or non-malignant respiratory disease31. Other studies, however, showed a high correlation of self-reported abstinence and biochemical validation32–35, even in pregnant women36, confirming the reliability of self-reported data. CO-measurement may even promote abstinence37. Our data confirm those of other observational trials, for example a CO-confirmed abstinence rate of 58.3% at the end of treatment (12 weeks) in two smoking cessation clinics in Barcelona, where treatment was highly comparable with the methods used in the CHOICES study, i.e. combining varenicline-prescription and cognitive-behavioral counseling23. The Health Improvement Network (THIN) database study found an abstinence rate of 49.5% at 5 months post-initiation of varenicline, which can be considered in line with our results (abstinence rate of 64.6% 3 months after varenicline initiation); both results are based on verbal report. Stapleton measured point prevalence abstinence after 4 weeks of treatment in an open-label study and found an abstinence rate of 80.3% (self-report) and 72.1% (CO-verified)29. The high compliance with treatment (a mean duration of 83 days, indicating an extended treatment-period for several participants) can also explain the elevated abstinence rate, since a positive association between treatment adherence and quit rates has clearly been demonstrated38,39. It seems that the supportive and personalized nature of the patient–counselor (physician, trained personnel) relationship promotes compliance and stimulates maintenance and abstinence. All counselors in the CHOICES study were either a member of a smoking cessation clinic or a primary care physician with a special interest in nicotine addiction. The counselors were therefore experienced in the guidance of smoking cessation, and were able to provide support including clinical interventions and advice that promoted adherence to varenicline treatment and smoking abstinence, for example coping strategies for unwanted side-effects, dosing adjustments, creating realistic outcome-related expectations, stimulating extended Observational European varenicline study Boudrez et al.

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treatment, and maintaining cessation motivation. The positive effect on the quit candidate provided by the personalized approach of an experienced tobacco specialist has been observed in previous research26 and other reallife data40. Abstinence rates in the CHOICES study were observed in the presence of several concomitant medications and comorbidities that were excluded in RCTs: elevated cholesterol, hypertension, and COPD. Recently, the efficacy and safety of varenicline was demonstrated in RCTs in patients with cardiovascular disease7 and COPD41. The current study data add to the results of these recent RCTs, indicating the effectiveness of varenicline in patients with important and chronic comorbidities. Participants in the CHOICES study experienced similar AEs to those that were recorded in the RCTs – nausea, insomnia, and sleep disorders – but these led to a small number of discontinuations (3.4%). Moreover, these AEs were rated as ‘severe’ in 51% of participants. A striking difference, however, concerns the incidence of the AEs, which was much lower in our observational study than in the RCTs: nausea was reported by 8.9% of patients in the CHOICES study versus430% in most RCTs; insomnia in 2.9% versus414% in RCTs; and abnormal dreams in 1.8% versus 410% in RCTs. AEs were collected at all patient contacts in a manner consistent with previous RCTs. This discrepancy may be explained by the lower frequency of doctor–patient contacts in routine smoking cessation management, triggering fewer reports of AEs than in the RCTs, which involved weekly follow-up visits. This explanation is supported by the safety data of the observational study by Ramon, which followed an identical follow-up schedule to the RCTs and found a pattern of incidence of AEs that resembled that found in RCTs23. No specific psychiatric AEs were reported in patients with preexisting depression or other psychiatric disorders. The personalized approach of the tobacco specialist, as previously mentioned, may be another explanation for the favorable incidence of AEs. There are a number of limitations to the CHOICES study. The lack of CO validation was considered, which is not uniformly used in clinical practice in Europe. Moreover, the divergent support resulting from the societal environment and policy towards smoking and smoking cessation in the participating countries may influence participation rates, compliance with the therapy, and possibly even quit rates.

Conclusions The results of this inter-European observational study demonstrate the effectiveness and safety profile of varenicline in an unselected population of smokers, consulting in daily clinical practice, and exhibiting a realistic clinical 774


picture of patients who have comorbidities and who are receiving treatment with other medications. The individual approach by experienced counselors, specialized in the area of nicotine addiction and familiar with the guidance of varenicline intake, seems to provide an important explanation for the high percentages of smoking abstinence observed in the CHOICES study, which supports the effectiveness of varenicline treatment in real-world clinical practice. The CHOICES study demonstrates that even in a real-world setting outside a clinical trial environment, varenicline is an effective smoking cessation aid with an acceptable safety profile.

Transparency Declaration of funding This study was funded by Pfizer Ltd, UK. H.B. and C.G. were participating investigators of the CHOICES study and both reviewed the manuscript at all stages of development. H.B. wrote the Introduction and Discussion sections. M. Messig is an employee of Pfizer Inc, New York, and M. Metcalfe is an employee of Pfizer Ltd, UK. Declaration of financial relationships H.B. receives research grants from Pfizer Inc; acts as a consultant for Pfizer Inc and is on the Speakers’ Bureau for Pfizer Inc. C.G. receives research grants from Novartis, GlaxoSmithKline, and Pfizer Inc. Acknowledgments Editorial support was provided by Fiona Nitsche, PhD, a medical writer of UBC Scientific Solutions, and funded by Pfizer Inc. List of investigators: Belgium: Prof. Dr Hedwig Boudrez; Dr Erik Ceulemans; Dr Andre Hutsebaut; Dr Luc Swinnen; Dr Marc Meysman; Dr Ludo Christiaen; Dr Alain Gemayel; Dr Nathalie Tilmant; Dr Kristiaan L. P. Nackaerts; Dr Norbert Van Mulders; Dr Francis Vrancken; Dr Philip Thibaut; Dr Pierre Bartsch; Prof. Laurence Galanti; Dr Pierre-Henri Arnould; Dr D. Lousbergh; Dr JeanPierre Hoengenaert; Dr Pierre Nys; Dr Robert Gerard; Dr Philippe Rochet; Dr Alfred Wuyard; Dr Bjorn Dieriks; Dr Eric Paquet; Dr Jean Roovers; Dr Veronique Lambert; Dr Guido Vereecken; Greece: Dr Marianna Kakoura; Dr Michael Patentalakis; Dr Stauroula Pataka; Stauroula Mpousmoukilia; Prof. Konstantinos Gourgouliani; Ioanna Mitrouska; Christina Gratziou; Stavros Konstantopoulos; Dimosthenis Mpouros; Michael Toumbis; Hungary: Dr Csaba Bocskei; Dr Zsuzsa Gyori; Dr Balazs Medgyasszay; Dr Zsuzsanna Cseke; Dr Anna Bartha; Dr Veronika Obbagy; Dr Katalin Csicsari; Dr Csilla Szabo; Dr Marta Beke; Dr Katalin Radich; Slovenia: Peter Kecelj; Cvetka Dragos Jancar; Stanislav Kajba; Blanka Bertalanic; Aleksander Stepanovic; Olga Doles; Mira Nikl Kravos.

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