Meta-analysis of the efficacy and safety of pantoprazole in the treatment and symptom relief of patients with gastroesophageal reflux disease – PAN-STAR

Introduction

Gastroesophageal reflux disease (GERD) is a common condition that develops when gastroesophageal reflux causes troublesome symptoms or complications. According to the Montreal definition, the diagnosis is established upon the presence of characteristic symptoms that the patient finds disturbing, regardless of their duration. Further classification of oesophageal and extra-oesophageal syndromes is based on diagnostic procedures that prove reflux of the gastric contents or the presence of characteristic and non-characteristic syndromes or complications [1]. The prevalence of GERD in industrially developed countries is about 20% with an incidence of 4.5 per 100,000 inhabitants. Both sexes are equally prone to the disease and morbidity increases with age. Twenty to forty percent of individuals experience reflux-related symptoms at least once monthly, 12% once a week, and 5% every day [1, 2]. Gastroesophageal reflux disease symptoms affect many aspects of patients’ lives including their quality of life, physical and mental well-being, and productivity [3]. Work absenteeism and increased use of health care resources result in high costs associated with GERD [4, 5]. Furthermore, epidemiological evidence suggests oesophageal adenocarcinoma is associated with prolonged GERD symptoms [6].
About 60% of primary care patients who suffer from untoward reflux symptoms lack endoscopically visible lesions in the oesophagus lining, while 35% of patients have reflux (erosive) oesophagitis (75% mild corresponding categories A and B according to Los Angeles classification, and 25% severe, corresponding category C or D according to the same classification). From 5% to 11% of patients can develop complications such as stricture, ulcer, or Barrett’s oesophagus [7].
State-of-the-art treatment involves proton pump inhibitors (PPI), which rapidly and successfully suppress the production of gastric acid, resulting in rapid symptom relief and high rates of oesophageal healing [8, 9]. Proton pump inhibitors treatment provides fast symptom relief but does not remove the main pathogenic factors, which leads to a high rate of relapse after successful treatment. Furthermore, PPI therapy success is a difficult task because the extent of mucosal damage has no relation with the severity of the symptoms.
The present meta-analysis of three clinical studies with similar protocols (all under the same name PAN-STAR), hereafter called PAN-STAR studies, aims to further assess pantoprazole (Nolpaza®) in clinical practice.

Aim

The primary goal of the PAN-STAR studies (Efficacy and safety of PANtoprazole in the treatment and SympTom relief in patients with gAstRoesophageal reflux disease (GERD)) was to establish the efficacy of treatment with 40 mg of pantoprazole and the effect of treatment duration on symptom control in patients with erosive reflux disease (ERD) and in those with non-erosive reflux disease (NERD). The secondary goal was to establish the effect of this treatment on the quality of life of patients with ERD and in patients with NERD. Additionally, analysis of adverse events due to pantoprazole treatment was performed.
The studies were supported by the KRKA pharmaceutical company. However, KRKA did not support this meta-analysis.

Material and methods

The three PAN-STAR clinical studies that formed the basis for this meta-analysis included 252 patients and were conducted in Slovenia, Poland, and the Russian Federation. The first patient was enrolled on 1st November 2009 and last patient on 6th December 2012. The trial and all of the amendments were reviewed by Independent National Ethics Committees (IECs) in all participating countries, appointed by corresponding regulatory authorities. Additionally, the study was also approved by the Local Ethics committees, where needed. EUdraCT code: 2009-017229-20.
All studies were multicentre, prospective, open-label, phase IV, conducted in 34 medical centres. Patients were treated for 4 to 8 weeks (depending on the fulfilment of healing criteria) with gastro-resistant tablets pantoprazole (Nolpaza®, produced by Krka, d. d. Novo mesto, Slovenia) in the dose of 40 mg. The tablets could not to be chewed or crushed but had to be swallowed whole one hour before a meal with some water.
The study population consisted of adult (above 18 years old) patients with gastroesophageal reflux disease of both genders. Upper endoscopy was performed at the time of inclusion in all patients to establish the presence or absence of ERD. During the study, the patients were not allowed to take any medications that could affect the results of the study (sucralfate, misoprostol, H2-receptor inhibitors, other proton pump inhibitors, ketoconazole, itraconazole). They were allowed to take antacids if necessary.
Patients with oesophageal or gastric malignancies, renal impairment (serum creatinine > 300 µmol/l), those positive for Helicobacter pylori infection, patients with GERD symptoms that had been unsuccessfully treated with proton pump inhibitors during a period of 6 months prior to inclusion, those with active ulcer disease (gastric, duodenal), and patients who had been treated with a proton pump inhibitor, H2-receptor inhibitor, sucralfate, or misoprostol 30 days or less prior to the first visit were not included in the study (Figure 1).
There were three visits during the study:
• Week 0 (initial visit): Upper endoscopy was performed in all included patients and the presence or absence of ERD was recorded. All patients started treatment with pantoprazole gastro-resistant tablets in a dose of 40 mg daily for 4 weeks.
• Week 4 (second visit): Patients were assessed for healing criteria fulfilment: absence of the primary symptom, heartburn, or regurgitation during the last 7 days before the control visit or its presence on not more than one day in the last week before the control visit, but in a mild form; no other symptom should be more marked than it was at the beginning of the treatment and should not be considered severe by the patient. Treatment with pantoprazole was stopped in all patients fulfilling the healing criteria. A visit for reassessment of remission was planned after 4 weeks.
Treatment with pantoprazole 40 mg daily was continued for the next 4 weeks in all patients that failed to fulfil the healing criteria.
• Week 8 (third visit): End of the study. During this last control visit both patients in remission after 4 weeks of treatment and patients treated with pantoprazole 40 mg for 8 weeks were examined.
All 252 patients were included in the safety analysis, and 249 patients were included in the efficacy analysis due to lack of data in 3 patients.
The severity of a symptom was assessed by patients on a scale from 0 to 3, where 0 means no symptoms; 1 – mild, occasional symptoms; 2 – moderate to severe symptoms; and 3 – severe symptoms. Patients assessed the total symptom severity score as a combined score on a scale from 0 to 3 for each symptom.
The quality of life in relation to gastroesophageal reflux disease was assessed by patients using the 1 to 10 rating scale, where 1 means worst quality of life (if the condition markedly reduces the patient’s ability for daily activities) and 10 means high quality of life (if the reflux disease does not interfere with the patient’s daily activities).
Because of the reasonably large sample, the asymptotic z-test was used to assess the difference between means of two variables measured in the same population. Analogously, an asymptotic 95%-confidence interval (CI) for the difference between means was used for interval estimation.

Results

Patient characteristics

The study population consisted of 96 (38%) males and 156 (62%) females with an average age of 48.7 ±15.8 years (min. 18 years, max. 82 years). The average body mass index was 27.1 ±4.89 kg/m2 (95% CI: 26.47‒27.67). The average body weight did not significantly change during the study, being 77.8 ±16.19 kg (95% CI: 75.8‒79.79) at the first visit and 77.03 ±16.21 kg (95% CI: 74.91‒79.16) at the third visit (after 8 weeks).
In total 54 (21.4%) patients reported tobacco smoking, and 198 (78.6%) patients were non-smokers. Two (0.8%) included patients consumed alcohol excessively, 6 (2.4%) patients regularly, 137 (54.4%) patients occasionally, and 107 (42.4%) patients did not consume alcohol.
At study entry 48 (19%) patients had been treated with antiulcer medication during the past 30 days: 46 (18.3%) patients had been given antacids, and 2 (0.8%) patients had been given H2-receptor inhibitors. In the month before entering the study, 204 (81%) patients had received no preliminary therapy with any antiulcer medication.
At the beginning of the studies 203 (80.6%) patients were without any concomitant therapy. Forty-nine (19.4%) patients were treated with concomitant therapy, among them 19 (7.5%) patients with acetylsalicylic acid (ASA) and 9 (3.6%) patients with non-steroidal anti-inflammatory drugs (NSAID). After 4 weeks of treatment 219 (86.9%) patients were without any concomitant therapy. From the 33 (13.1%) patients who were still receiving concomitant therapy, 11 (4.4%) patients were treated with ASA and 7 (2.8%) patients with NSAID. After 8 weeks of treatment, there were 27 (10.7%) patients with concomitant therapy, among them 8 (3.2%) patients treated with ASA and 4 (1.6%) patients with NSAID. Two hundred and twenty-five (89.3%) patients received no concomitant therapy.
At the time of enrolment 139 (55%) patients had had the present symptomatic condition for more than 2 months, 43 (17%) patients 1 to 2 months, 29 (12%) patients 3 to 4 weeks, 28 (11%) patients 1 to 2 weeks, and 13 (5%) patients up to 1 week.
On the day of enrolment 10 (4%) patients had had the present reflux disease more than 2 years, 139 (55%) patients 1 to 2 years, 46 (18%) patients 6 to 12 months, 24 (10%) patients up to 6 months, and for 33 (13%) patients it was the first occurrence.
Score A oesophagitis according to Los Angeles classification was found in 92 (37%) patients, score B in 41 (16%) patients, and score C in 2 (1%) patients. In 117 (46%) patients no endoscopically detectable changes of the oesophageal lining were found – meaning no oesophagitis.
Hiatal hernia was found in 114 (45%) patients, 135 (54%) patients were without hiatal hernia, and we do not have data for 3 (1%) patients.
In 13 (5%) patients the presence of a Helicobacter pylori infection was confirmed by a positive rapid urease test. Nevertheless, these patients were included in ITT analysis. In other patients a negative urease test was found.
The study population had the following signs and symptoms: 247 (98%) patients had heartburn, 213 (85%) patients regurgitation, 80 (32%) patients dysphagia, 114 (45%) patients retrosternal pain, 152 (60%) patients epigastric pain, 152 (60%) patients eructation, 95 (38%) patients nausea, 57 (23%) patients cough, and 4 (2%) patients had other signs and symptoms.
The leading symptom was the symptom that was described by the patient as the most frequent and the most disturbing, and was also the most marked; 1 patient could have one or more leading symptom/s. Heartburn was the most frequently occurring leading symptom, experienced by 233 (92%) patients, 150 (60%) patients experienced regurgitation, 16 (6%) patients dysphagia, 33 (13%) patients retrosternal pain, 65 (26%) patients epigastric pain, 50 (20%) patients eructation, 11 (4%) patients nausea, 11 (4%) patients cough, and 4 (2%) patients experienced other signs and symptoms as leading symptoms.
At the beginning of the study, there were 50 (20%) patients with only one leading symptom, 108 (43%) patients with two leading symptoms, 76 (30%) patients with three leading symptoms, 11 (4%) patients with four leading symptoms, and 7 (3%) patients with five leading symptoms.

Treatment evaluation

Patients reaching the healing criteria

Reaching the healing criteria was defined as the absence of the primary symptom (heartburn or regurgitation) during the last 7 days before the control visit or its presence on not more than 1 day in the last week before the control visit, but in a mild form. No other symptom should be more marked than it was at the beginning of the treatment, i.e. it must not be severe.
After 4 weeks of treatment, 110 (44%) patients out of 249 fulfilled the healing criteria, and after 8 weeks of treatment 164 (66%) patients out of 249 fulfilled the healing criteria. If we exclude the patients with incomplete data, then 110 (45%) patients out of 246 fulfilled the healing criteria after 4 weeks of treatment and 164 (70%) patients out of 234 after 8 weeks of treatment. For 15 patients, there were not enough data by which the healing criteria could be determined (Figure 2).
After 8 weeks of treatment significantly more (p < 0.0001) erosive patients reached the healing criteria than non-erosive patients (Figure 3).

Total severity score of leading symptoms

The total severity score of leading symptoms was 4.86 ±2.31 (95% CI: 4.57‒5.15) at the first visit as assessed by 249 patients, 1.11 ±1.45 (95% CI: 0.92‒1.29) at the second visit as assessed by 245 patients, and 0.54 ±1.07 (95% CI: 0.4‒0.67) at the third visit as assessed by 233 patients. The improvement in the total severity score of leading symptoms was significant (p < 0.0001) throughout the study, indicating that pantoprazole had a continuous positive effect on the severity of leading symptoms during 8 weeks of treatment (Figure 4).
In the group of patients in remission after 4 weeks of treatment (and stopping treatment after 4 weeks), a sustained improvement in the total severity score of leading symptoms was demonstrated at the control visit after 8 weeks. The GERD patients treated for 8 weeks clearly reached a further improvement in the total severity score of leading symptoms after 8 weeks of treatment compared to 4 weeks of treatment (Figure 4).
The total severity score of leading symptoms was decreased to the same extent in both erosive and non-erosive patients (Figure 5).

Individual symptoms

The average score for the heartburn symptom was 2.17 ±0.82 (95% CI: 2.07‒2.27) at the first visit as assessed by 249 patients, 0.55 ±0.71 (95% CI: 0.46‒0.64) at the second visit as assessed by 245 patients, and 0.26 ±0.54 (95% CI: 0.19‒0.33) at the third visit as assessed by 233 patients.
The average score for the regurgitation symptom was 1.6 ±0.99 (95% CI: 1.48‒1.73) at the first visit assessed by 249 patients, 0.44 ±0.66 (95% CI: 0.36‒0.52) at the second visit assessed by 245 patients, and 0.26 ±0.57 (95% CI: 0.18‒0.33) at the third visit assessed by 233 patients.
The improvement in heartburn and regurgitation symptoms was significant (p < 0.0001) throughout the study, indicating that pantoprazole also had a continuous positive effect on heartburn during 8 weeks of treatment.
Next to symptoms such as heartburn and regurgitation, dysphagia, retrosternal pain, epigastric pain, eructation, nausea, and cough were also significantly reduced during the PAN-STAR studies.

Total symptoms severity score

The total symptoms severity score was 8 ±4.14 (95% CI: 7.49‒8.52) at the first visit as assessed by 249 patients, 2.03 ±2.42 (95% CI: 1.73‒2.33) at the second visit as assessed by 245 patients, and 1 ±1.8 (95% CI: 0.76‒1.23) at the third visit as assessed by 233 patients.
The improvement in all symptoms severity score was significant (p < 0.0001) throughout the study, indicating that pantoprazole had a continuous positive effect on the severity of all symptoms together during 8 weeks of treatment (Figure 6).
In the group of patients in remission after 4 weeks of treatment (and stopping treatment after 4 weeks), a sustained improvement in the total symptoms severity score was demonstrated at the control visit after 8 weeks. The GERD patients treated for 8 weeks clearly reached a further improvement in the total symptoms severity score after 8 weeks of treatment compared to 4 weeks of treatment (Figure 6).
The total symptoms severity score was decreased to the same extent in both erosive and non-erosive patients (Figure 7).

The effect of treatment on the patient’s quality of life

The average score for the quality of life was 4.65 ±2.06 (95% CI: 4.4–4.91) at the first visit as assessed by 249 patients, 7.61 ±2.01 (95% CI: 7.36–7.86) at the second visit as assessed by 245 patients, and 8.41 ±1.83 (ACI: 8.18, 8.65) at the third visit as assessed by 234 patients.
The average score for the quality of life gradually increased until the end of the study. The increase was significant (p < 0.0001), indicating that pantoprazole has a continuous positive effect on the quality of life during 8 weeks of treatment (Figure 8).
In the group of patients in remission already after 4 weeks (and stopping treatment after 4 weeks) weeks, a sustained improvement in the quality of life was demonstrated at the control visit after 8 weeks. The GERD patients treated for 8 weeks clearly reached a further improvement in quality of life after 8 weeks of treatment compared to 4 weeks of treatment (Figure 8).
The quality of life was increased to the same extent in both erosive and non-erosive patients after 4 weeks. However, after 8 weeks of treatment a significant difference in improvement in the quality of life (p < 0.05) was demonstrated in erosive patients compared to non-erosive patients (Figure 9).

Safety evaluation

The criterion for the safety evaluation was the overall incidence of drug-related adverse events (adverse reactions). All 252 patients were included in the safety analysis.
Treatment with pantoprazole 40 mg was well tolerated. More than 90% of patients throughout the whole study period were without adverse events. Adverse reactions with causal relationship to the study medication appeared in 18 patients (7.1% of patients). The most common adverse reactions were constipation (5 patients, 2%), nausea (4 patients, 1.6%), flatulence (3 patients, 1.2%), hypersensitivity (3 patients, 1.2%), and headache (3 patients, 1.2%). Four patients discontinued the treatment due to adverse reactions after the initial visit.

Discussion

A number of multicentre, controlled, randomised studies have demonstrated that pantoprazole in daily doses of 40 mg administered for 4–8 weeks is an optimal dosing regimen in non-erosive reflux disease and mild to moderate erosive reflux disease, compared to histamine-2-receptor antagonists (H2RAs) [10–14]. The rate of endoscopy confirmed that healing was significantly higher in patients on pantoprazole therapy compared to that observed with H2RA therapy [10, 12, 15–19]. Pantoprazole was approved by the FDA in 2000 for the treatment of erosive esophagitis associated with GERD. It has been used in more than 100 different countries worldwide [20].
The efficacy and safety of pantoprazole for the treatment and symptom relief in patients with gastroesophageal reflux disease were studied in three multicentre, open labelled, prospective, phase IV PAN-STAR studies. The target population was selected according to typical GERD symptoms (troublesome heartburn and/or regurgitation) in all three clinical trials. Reported reflux symptoms duration was 1 to 2 years in half of the patients and 4% of included patients were symptomatic for more than 2 years. No endoscopically detectable changes of the oesophageal lining were found in 46% of patients.
Gastroesophageal reflux disease symptom profile did not differ in patients with ERD and in those with NERD. Recent studies have demonstrated that patients with NERD are more difficult to manage than those with ERD and that progression to ERD is relatively uncommon in these patients [21]. Two hundred fifty-two patients were included in this meta-analysis (efficacy analysis was performed in 249). The studied population had a mean age of 48.7 ±15.8 years, and 62% of included patients were female. A relatively large proportion of included patients were non-smokers (198 patients, 78.6%), while only 107 (42.4%) patients denied drinking alcohol. One third of patients had accompanying diseases, of which the majority (57 patients; 22.6%) had arterial hypertension; 19.4% of patients had concomitant therapy.
Little is known about the possible differences in the therapeutic response to the PPIs with regard to geographical and ethnic differences in patients with GERD. Small differences in the interpretation of symptoms can have a major influence on the trial results. There is frequent disagreement between everyday clinical practice and reported clinical trial results, which can be attributed to studied endpoints and selected patient population [22, 23].
A number of behavioural factors are thought to trigger GERD. Many studies identified a significant association between GERD, smoking, and alcohol consumption [24, 25]. Furthermore, a number of significant associations were demonstrated with the use of prescription medications such as NSAIDs, anticholinergic drugs, nitrates, benzodiazepines, and calcium antagonists [2].
In general, the cure rates in GERD and the disappearance of clinical symptoms depend on baseline symptom severity and the patients’ compliance with the PPI treatment [26]. The time to resolution of heartburn and other symptoms did not differ significant between different PPIs [27].
In different clinical studies using different PPIs, complete disappearance of clinical symptoms at 8 weeks of treatment was reported in 65–67% of the treated patients, and endoscopic cure was observed in 85–90% of the patients. No significant differences between proton pump inhibitors were observed in the rate of clinical remission of GERD and cure of ERD [28]. Seventy-thirty-two percent of GERD patients have resistant and troublesome symptoms of heartburn and regurgitation regardless of PPI therapy [29].
The results in the PAN-STAR studies show that pantoprazole in a dose of 40 mg was found to be highly effective and safe in the treatment of GERD. In the intention-to-treat analysis, 44% of patients met the healing criteria after 4 weeks of treatment, and this number increased to 66% after a further 4 weeks of treatment. When excluding the patients with incomplete data, 110 (45%) patients out of 246 fulfilled the healing criteria after 4 weeks of treatment and 164 (70%) patients out of 234 after 8 weeks of treatment. The average total symptom severity score was significantly reduced after 4 weeks of treatment and decreased even further by 8 weeks (including 40% of patients in remission, who stopped treatment with pantoprazole after 4 weeks of treatment). The average symptom severity score at enrolment was 2.03 (on the scale 0–3) and 1.00 at 8 weeks. 98.4% of patients receiving pantoprazole for 4 weeks experienced significant relief of leading symptoms with the average score of 1.11. 93.6% of patients reported average leading symptom severity score of 0.54 after 8 weeks of treatment. Both treatment durations were associated with a significant increase in the quality of life.
Pantoprazole 40 mg demonstrated a continuous improvement of the relief of symptoms and the quality of life of GERD patients during 8 weeks of treatment, showing that GERD patients with persisting symptoms benefit from prolonging treatment to 8 weeks. At the same time, no significant increase in the severity of symptoms and no significant decrease in the quality of life were found 4 weeks after they discontinued the therapy in patients who fulfilled the healing criteria after 4 weeks of treatment. Symptom resolution rate after 4 and 8 weeks, as well as quality of life improvement, were lower in patients with NERD when compared to patients with oesophagitis. Several other recent studies report similar findings, possibly indicating that patients with NERD are a more heterogeneous population than patients with erosive disease [30, 31].
Proton pump inhibitors are generally very well tolerated, and they are rarely associated with adverse reactions. The most common adverse effects of treatment in this group of medicines are headache, nausea, diarrhoea, abdominal pain, fatigue, and dizziness [32]. Diarrhoea was observed in 4.5% of the patients during a 1-year treatment with pantoprazole, nausea in 2.7% of the patients, vomiting in 2.3% of the patients, and dizziness in 1.8% of the patients [33]. Pantoprazole was demonstrated to have a favourable tolerability profile in a British post-authorisation surveillance study in 11,541 patients, where adverse events were reported in only 107 patients. The most significant adverse reactions were diarrhoea, nausea, headache, and dizziness [34]. Recently published data have demonstrated that daily pantoprazole maintenance therapy for up to 15 years for severe acid peptic disease is effective and well tolerated with no identified safety concerns. The moderate pantoprazole-induced hypergastrinaemia was not associated with any clinically relevant transformation of gastric mucosa [35].
The results of this meta-analysis agree with these findings. More than 90% of patients were without adverse events throughout the whole study. Adverse reactions with causal relationship to the study drug appeared in 7.1% of patients. The most common adverse reactions were constipation (5 patients, 2%), nausea (4 patients, 1.6%), flatulence (3 patients, 1.2%), hypersensitivity (3 patients, 1.2%), and headache (3 patients, 1.2%). Only 4 patients discontinued the treatment due to adverse events related to the pantoprazole treatment.

Conclusions

The results of the present meta-analysis of the PAN-STAR clinical studies show that pantoprazole 40 mg was associated with complete relief of GERD related symptoms in the majority of patients with ERD and NERD. In patients without complete relief of symptoms the severity of symptoms was significantly reduced. Furthermore, pantoprazole 40 mg significantly improved the quality of life of treated patients and was very well tolerated throughout the whole study. Therefore, this meta-analysis suggests that pantoprazole 40 mg once daily is an effective and well tolerated choice for providing symptom relief of patients with GERD.

Acknowledgments

Source of funding: Krka, d. d., Novo mesto.

Conflict of interest

The authors have received fees from KRKA for performing PAN-STAR studies. No payments were made to authors for performing this meta-analysis and writing of this article.

List of investigators

Investigators from Slovenia
1. prof. dr. Borut Štabuc, University Medical Centre Ljubljana, principal investigator
2. prim. asist. dr. Borut Kocijančič, University Medical Centre Ljubljana
3. Manfred Mervic, University Medical Centre Ljubljana
4. Rado Janša, University Medical Centre Ljubljana
5. Andrej Gruden, University Medical Centre Ljubljana
6. Živa Mrevlje, University Medical Centre Ljubljana
7. Samo Plut, University Medical Centre Ljubljana
8. David Drobne, University Medical Centre Ljubljana
9. Katja Novak, University Medical Centre Ljubljana
10. Alojz Šmid, University Medical Centre Ljubljana
11. Aljaž Repše, University Medical Centre Ljubljana
12. Nataša Smrekar, University Medical Centre Ljubljana
13. Branko Gregorič, General Hospital Novo mesto
14. Marjan Gorenc, General Hospital Novo mesto
15. Boštjan Gorjup General Hospital Novo mesto
16. Blaž Berger, General Hospital Izola
17. Tamara Marušič, General Hospital Izola
18. Bojana Luštrek, General Hospital Izola
19. Marija Humek Petelinc, General Hospital Brežice
20. Primož Jovan, General Hospital Jesenice
21. prim. Milan Stefanovič, Diagnostic Centre Vila Bogatin Bled
22. Jasna Volfand, Diagnostic Centre Bled
23. Zdravko Tošović, Diagnostic Centre Bled
24. Ljiljana Ljepovič, Diagnostic Centre Bled
25. Miran Drenovec, Diagnostic Centre Bled
26. Dejan Urlep, Diagnostic Centre Bled
27. Jurij Bednarik, General Hospital Šempeter
28. Marko Klančič, General Hospital Šempeter
29. Bor Urbančič, General Hospital Šempeter
30. Stanislav Benedik, Private practice in Kranj
31. mag. Jože Seljak, Private practice in Nova Gorica
32. Boris Škofic, Hospital Golnik
33. Renata Šibli, General Hospital Celje
34. Boštjan Birsa, General Hospital Celje
35. Rajko Kneževič, General Hospital Celje
36. Barbara Sodin, General Hospital Celje
37. Tadeja Pačnik Vižintin, General Hospital Celje
38. Jure Zupan, General Hospital Celje
39. Marija Žnidaršič, General Hospital Celje
40. Bojan Glavnik, Private practice Endomed, Celje
41. Enriko Plevnik, General Hospital Slovenj Scorec
42. Vladimir Natek, General Hospital Slovenj Scorec
43. Zdenko Kikec, General Hospital Slovenj Scorec
44. Klemen Mojškerc, General Hospital Slovenj Scorec
45. Miroslav Vujasinović, General Hospital Slovenj Scorec
46. Sonja Puhr Moličnik, Private practice in Slovenj Scorec
47. Zdenka Čerk Speiser, General Hospital Trbovlje
48. Nataša Brglez Jurečič, General Hospital Trbovlje
49. Alenka Forte, Private practice Helix in Trbovlje
50. prof. dr. Bojan Tepeš, Private practice Abacus in Rogaška Slatina
51. mag. Zoran Stanišič, Medical Centre Rogaška Slatina
52. Anita Kek Ljubec, Medical Centre Rogaška Slatina
53. Darko Košutić, Private practice in Rogaška Slatina
54. Borut Rijavec, Hospital Topolšica
55. prof. dr. Pavel Skok, University Medical Centre Maribor
56. Maksimilijan Pocajt, University Medical Centre Maribor
57. Andreja Ocepek, University Medical Centre Maribor
58. Davorin Čeranič, University Medical Centre Maribor
59. Davorin Dajčman, University Medical Centre Maribor
60. prim. asist. Cvetka Pernat, University Medical Centre Maribor
61. mag. Žarko Pinter, Private practice Archimed, d.o.o, Maribor
62. mag. Maja Šeruga, General Hospital Murska sobota
63. Stana Šutulovič, General Hospital Murska sobota
64. Miran Gerič, General Hospital Murska sobota
65. Dejan Majc, General Hospital Murska sobota
66. Tatjana Puc Kous, Private practice in Medical Centre Radenci
67. Matjaž Brenčič, General Hospital Ptuj
68. Branko Vukasovič, General Hospital Ptuj
69. asist. Željko Perdija, General Hospital Ptuj

Investigators from Poland
1. prof. dr. hab. med. Andrzej Dąbrowski, Medical University of Bialystok, principal investigator
2. dr n. med. Grażyna Jurkowska, Medical University of Bialystok
3. Ewa Turecka-Kulesza, Medical University of Bialystok
4. prof. Jerzy Gil, Military Institute of Medicine in Warsaw
5. dr Michał Florek, Military Institute of Medicine in Warsaw
6. dr Tomasz Stelmaszuk, Military Institute of Medicine in Warsaw
7. dr Przemysław Dyrla, Military Institute of Medicine in Warsaw

Investigators from the Russian Federation
1. Leonid Lazebnik, Moscow State University of Medicine and Dentistry named after A. I. Evdokimov, principal investigator
2. Dmitriy Bordin, State Health Care Institution of Moscow city, Central Research and Development Institute of Gastroenterology, principal investigator
3. Sayar Abdulkhakov, State Educational Institution of the Higher Professional Education, Kazan State Medical University of Roszdrav
4. Elena Eremina, State Educational Institution of the Higher Professional Education, Mordovsk State University of N.P. Ogarev, Federal Agency of Education
5. Natalya Zakharova, Sankt-Petersburg State Health Care Institution, Municipal Hospital No. 26
6. Igor Ivanikov, Federal State Institution, Central Clinical Hospital with the Out-patient Clinic of Department of Presidential Affairs of the Russian Federation
7. Nonna Nikolaeva, State Educational Institution of the Higher Professional Education, Krasnoyarsk State Medical University of the prof. V.F. Voyno-Yaseneckiy, the Ministry of Health and Social Development of Russia

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Received: 21.04.2017
Accepted: 23.05.2017