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Pantoprazole BY1023/DE004 492/2007 (1.0) 1 of 7

Summary of Clinical Study Results (Version 1.0)

Study Protocol BY1023/DE004

Clinical Study Report 492/2007

Title of the study: Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg od for 7 days.

EudraCT Number: 2005-004856-11

Clinicaltrials.gov Identifier: NCT00326027

Version Date: 21-July-2008



Pantoprazole BY1023/DE004 492/2007 (1.0) 2 of 7

Title of the study: Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg od for 7 days.

Investigator and study centers: The study was a multi-center study in 35 participating centers in Germany. Only 9 centers thereof were active and recruited patients. Coordinating investigator(s): Prof. Dr Joachim Mössner, Universitätsklinikum Leipzig Liebigstr. 20, 4103 Leipzig, Germany Publication (reference): Not applicable. Studied period: 10-OCT-2006 to 02-JUL-2007 Clinical phase: III Objectives: This was the first study to prove fast symptom reduction in hospitalized patients suffering from NERD (non-erosive gastroesophageal reflux disease) or GERD (gastroesophageal reflux disease) after 1 day of treatment with pantoprazole 20 mg (NERD) or with pantoprazole 40 mg (GERD A-D). Methodology: Open, multi-center, stratified (GERD/NERD). NERD: 7 days treatment with pantoprazole 20 mg GERD A-D: 7 days treatment with pantoprazole 40 mg



Pantoprazole BY1023/DE004 492/2007 (1.0) 3 of 7 No. of patients planned and analyzed: A number of 350 patients (at least 18 years of age) in 35 study centers were planned to be included into the ITT (intention-to-treat) population to obtain 285 patients PP (per-protocol). Due to very slow recruitment only 29 patients in 9 study centers could be included in the study. Therefore, the study was terminated because it became obvious that the target number of patients would not be reached in a reasonable time. One patient did not take any medication, thus 28 patients were in the safety set. Analyzed set

Total set Safety set

Group NERD (pantoprazole 20 mg) 7 7

Group GERD (pantoprazole 40 mg) 21 21

Missing 1 -

Total 29 28

Diagnosis and main criteria for inclusion: • written informed consent by the patient for study participation, prior to protocol

specific procedures;

• inpatients of at least 18 years of age (hospitalization during the entire study period of 7 days is mandatory);

• symptomatic (heartburn, acid regurgitation or dysphagia for at least 1 day since admission to the hospital) NERD or GERD (LA [Los Angeles] grade A-D).

Test product, dose, mode of administration, batch no.: Pantoprazole 20 mg, once daily, oral, 00300101 Pantoprazole 40 mg, once daily, oral, 00300102 Reference product, dose, mode of administration, batch no.: Not applicable.



Pantoprazole BY1023/DE004 492/2007 (1.0) 4 of 7 Duration of treatment: 7 days of treatment with either pantoprazole 20 mg (NERD patients) or pantoprazole 40 mg (GERD patients) Criteria for evaluation: Primary variable

• symptom reduction from reflux disease related symptoms measured as assessed by ReQuest™-GI after 1 day of treatment.

For the primary variable a separate analysis was done for the subgroups NERD and GERD. Secondary variables

• symptom reduction from reflux disease related symptoms as assessed by ReQuest™-GI after 2, 3, 4, 5, 6 and 7 days of treatment were analyzed analogous to the primary variable;

• the symptom relief rates as assessed by ReQuest™ after 7 days of treatment and the respective 95% confidence intervals were calculated;

• the relief rates from reflux disease related complaints after 7 days of treatment (as assessed by the investigator) and the respective 95% confidence intervals were calculated.

Five further secondary variables could not be analyzed as planned due to the low number of patients. Statistical methods: Due to the low number of patients all analyses were based on the safety set. Only descriptive analyses have been performed for all efficacy and safety variables.



Pantoprazole BY1023/DE004 492/2007 (1.0) 5 of 7 SUMMARY – CONCLUSIONS Demography and baseline characteristics Demographic and other baseline characteristics by gender (safety set, N = 28)

Demographic variable Overall N = 28

Male N = 15

Female N = 13

Age [years], mean (SD) 66.79 (14.11) 57.61 (11.63) 77.39 (7.94)

Height [cm], mean (SD) 169.68 (10.74 177.20 (8.65) 161.00 (4.47)

Weight [kg], mean (SD) 75.46 (13.15) 80.20 (12.63) 70.00 (11.94)

BMI [kg/m²], mean (SD) 26.22 (3.90) 25.58 (3.72) 26.96 (4.11)

N: number of patients, SD: standard deviation

Study results Efficacy results A symptom reduction was observed after one day of treatment as assessed by all three ReQuestTM scores (ReQuestTM-GI, ReQuestTM-WSO, ReQuestTM total score) in both treatment groups. With regard to the primary variable, ReQuestTM-GI, the pre-post difference was numerically higher in the NERD group treated with pantoprazole 20 mg (-2.20) than in the GERD group treated with pantoprazole 40 mg (-0.99). Also with regard to the course of symptoms during the 7 days of treatment (secondary variables), there was a reduction of symptoms over time. Due to the very low number of patients and thus the exploratory character of the analyses, it is not possible to draw any clinical relevant conclusion concerning the primary and secondary variables. Safety results No death or SAEs were observed during the course of the study. 5 treatment-emergent AEs were experienced by 5 out of 28 patients (17.9%) included in the safety set. In the P20 group, 1 patient experienced 1 AE and in the P40 group, 4 patients experienced 4 AEs.



Pantoprazole BY1023/DE004 492/2007 (1.0) 6 of 7 Treatment-emergent AEs (safety set N = 28)

P20 group (N = 7)

P40 group (N = 21)

Obs % Obs % AEs 1 14.3 4 19.0

SAEs - - - -

Deaths - - - -

AEs with causalitya suggested by the investigator

- - - -

AEs leading to discontinuation - - 1 4.8 a AEs assessed by the investigator as “likely” ore “definitely” related to the study medication. AE = adverse event, N = number of patients, Obs = number of patients with events, P20 group = patients in stratum NERD (pantoprazole 20 mg), P40 group = patients in stratum GERD (pantoprazole 40 mg), SAE = serious adverse event As assessed by the investigator, 3 (60%) of the treatment-emergent AEs showed ‘unrelated’ relation to the study medication (all in the P40 group: GGT increased, Cholecystolithiasis, Gastroenteritis). 2 AEs (40%) were assessed as ‘unlikely’ related to the study medication (1 AE in P20 group: Meteorism; 1 AE in P40 group: Allergic reaction). No ‘likely’ or ‘definite’ relation to the study medication was documented. The intensity of AE symptoms as reported by the investigator was ‘mild’ for 1 case (1 patient of the P20 group ), ‘moderate’ for 3 cases (3 patients of the P40 group ) and ‘severe’ for 1 case (1 patient of the P40 group ). 1 patient (3.6% of the safety set) of the P40 group prematurely discontinued the study due to the treatment emergent AE allergic reaction. According to the investigators, none of the respective AE symptoms was assessed as ‘definitely’ related to the study medication. No vital sign parameter assessed showed systematically or relevant changes during the course of the study. In conclusion, both doses of pantoprazole were well tolerated and safe.



Pantoprazole BY1023/DE004 492/2007 (1.0) 7 of 7 Conclusions: Due to the low number of patients only descriptive analyses of efficacy and safety could be applied. However, numerical trends were observed indicating a fast symptom reduction in hospitalized patients suffering from GERD and NERD and treated with pantoprazole over 7 days. Pantoprazole 20 mg and pantoprazole 40 mg were well tolerated and safe during a reatment duration of 7 days. The present study did not reveal any suspicion of hitherto unknown risks for the intake of pantoprazole.

ALTANA Pharma AG

Byk-Gulden-Str. 2 78467 Konstanz Germany

T: +49 (0)7531 / 84-2105 F: +49 (0)7531 / 84-2105 Sabine Weitzmann

STUDY PROTOCOL

» PROFI-Study«

Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease

treated with pantoprazole 20 or 40 mg o.d. for 7 days

(BY1023/DE004)

EudraCT No. 2005-004856-11

Phase III

open, multicenter, stratified Copyright: All rights reserved. This protocol is the property of sponsor ALTANA Pharma Group, hereafter referred to as Sponsor. The disclosure to third persons, changes or reproduction in any form or by any means without previous written permission of the owner is not permitted.

Study Protocol BY1023/DE-004, Final Version 1.0, December 20, 2005 Page 1 of 77

TABLE OF CONTENTS List of abbreviations and definitions of terms 5 List of addresses 7 1 SUMMARY___________________________________________________ 9 2 INTRODUCTION ____________________________________________ 12 2.1 THE INVESTIGATIONAL PRODUCT PANTOPRAZOLE _____________________ 12 2.2 THE COMPARATOR PRODUCT _____________________________________ 13 2.3 BACKGROUND OF THE CLINICAL STUDY _____________________________ 13 2.4 RISK / BENEFIT CONSIDERATION___________________________________ 14 3 STUDY OBJECTIVE _________________________________________ 14 3.1 PRIMARY VARIABLE ____________________________________________ 14 3.2 SECONDARY VARIABLES _________________________________________ 14 4 STUDY DESIGN AND PATIENT POPULATION _________________ 15 4.1 STUDY DESIGN ________________________________________________ 15 4.2 STUDY DURATION ______________________________________________ 15 4.3 PATIENT POPULATION ___________________________________________ 15 4.4 INCLUSION CRITERIA____________________________________________ 15 4.5 EXCLUSION CRITERIA ___________________________________________ 16 4.6 INTERIM EXCLUSION CRITERIA ____________________________________ 18 4.7 DISCONTINUATION CRITERIA _____________________________________ 18 5 STUDY MEDICATION, DOSAGE AND STORAGE _______________ 19 5.1 GENERAL_____________________________________________________ 19 5.2 LABELING OF STUDY MEDICATION _________________________________ 19 5.3 STORAGE_____________________________________________________ 19 5.4 DOSAGE REGIMEN AND INTAKE ___________________________________ 20 5.5 START OF TREATMENT AND INSTRUCTION OF PATIENTS _________________ 20 5.6 BLINDING ____________________________________________________ 21 5.7 RANDOMIZATION AND EMERGENCY CARDS __________________________ 21 5.8 ACCOUNTABILITY OF STUDY MEDICATION ___________________________ 21 5.9 SUPPORTIVE AND CONCOMITANT MEDICATION _______________________ 22 5.10 NON-PERMITTED MEDICATION ____________________________________ 22 5.11 PERMITTED MEDICATION ________________________________________ 22 5.12 OVERDOSE ___________________________________________________ 23 6 METHODS AND CONDUCT OF THE STUDY ___________________ 24 6.1 STUDY SCHEDULE ______________________________________________ 24 6.2 METHODS ____________________________________________________ 25 6.2.1 PATIENT INFORMATION SHEET AND INFORMED CONSENT PROCEDURE______ 25 6.2.2 MEDICAL HISTORY AND PHYSICAL EXAMINATION _____________________ 25 6.2.3 ENDOSCOPY __________________________________________________ 25 6.2.4 GRADES OF REFLUX ESOPHAGITIS ACCORDING TO LOS ANGELES (LA)

CLASSIFICATION _______________________________________________ 27 6.2.5 SYMPTOM ASSESSMENT _________________________________________ 28


6.2.5.1 SYMPTOM ASSESSMENT BY THE INVESTIGATOR _______________________ 28 6.2.5.2 SYMPTOM ASSESSMENT BY THE PATIENT ____________________________ 29 6.2.5.3 INFORMATION FLOW ____________________________________________ 31 6.2.6 LABORATORY TESTS ____________________________________________ 31 6.2.6.1 BLOOD SAMPLES _______________________________________________ 31 6.2.6.2 PREGNANCY TEST ______________________________________________ 33 6.2.6.3 URINALYSIS___________________________________________________ 33 6.2.6.4 DETERMINATION OF HELICOBACTER PYLORI STATUS ____________________ 34 6.3 CONDUCT OF THE STUDY_________________________________________ 34 6.3.1 BASELINE VISIT (V0) ___________________________________________ 34 6.3.2 FINAL VISIT (V1) ______________________________________________ 34 6.3.5 UNSCHEDULED VISITS___________________________________________ 35 6.3.6 PREMATURE TERMINATION FROM THE STUDY_________________________ 35 7 ADVERSE EVENTS __________________________________________ 36 7.1 DEFINITION AND DOCUMENTATION_________________________________ 36 7.2 SERIOUS ADVERSE EVENTS_______________________________________ 38 7.3 NOTIFICATION OF THE INDEPENDENT ETHICS COMMITTEE / INSTITUTIONAL

REVIEW BOARD AND THE HEALTH AUTHORITIES ______________________ 39 7.4 FOLLOW-UP OF ADVERSE EVENTS__________________________________ 40 7.5 FOLLOW-UP OF SERIOUS ADVERSE EVENTS __________________________ 41 7.6 PREGNANCY __________________________________________________ 41 8 BIOSTATISTICAL METHODS ________________________________ 43 8.1 GENERAL_____________________________________________________ 43 8.2 STATING THE PROBLEM__________________________________________ 43 8.3 STUDY DESIGN ________________________________________________ 43 8.4 ANALYSIS SETS AND TYPES OF ANALYSES ___________________________ 43 8.4.1 ANALYSIS SETS ________________________________________________ 43 8.4.1.1 TOTAL SET ___________________________________________________ 43 8.4.1.2 FULL ANALYSIS SET ____________________________________________ 44 8.4.1.3 PER PROTOCOL SET_____________________________________________ 44 8.4.1.4 SAFETY SET___________________________________________________ 45 8.4.2 TYPE OF ANALYSIS _____________________________________________ 45 8.4.2.1 INTENTION-TO-TREAT (ITT) ANALYSIS _____________________________ 45 8.4.2.2 PER PROTOCOL (PP) ANALYSIS____________________________________ 45 8.4.2.3 ANALYSIS OF SAFETY ___________________________________________ 45 8.5 PRIMARY, CO-PRIMARY AND KEY-SECONDARY VARIABLE(S) ____________ 45 8.6 TESTING PROCEDURE ___________________________________________ 46 8.7 STATISTICAL ANALYSIS OF PRIMARY VARIABLE, CO-PRIMARY AND KEY-

SECONDARY VARIABLE(S) AND STATISTICAL HYPOTHESIS_______________ 46 8.8 INTERIM ANALYSIS _____________________________________________ 46 8.9 SAMPLE SIZE CONSIDERATIONS ___________________________________ 46 8.10 RANDOMIZATION_______________________________________________ 46 8.11 SECONDARY VARIABLES AND THEIR STATISTICAL ANALYSES ____________ 46 8.12 SUBGROUP ANALYSES___________________________________________ 47 8.13 CLINICAL LABORATORY _________________________________________ 48 8.14 ADVERSE EVENTS ______________________________________________ 48


8.15 HEALTH ECONOMICS AND HEALTH RELATED QUALITY OF LIFE ___________ 48 8.16 HANDLING OF MISSING VALUES ___________________________________ 48 8.17 DATA ENTRY AND VALIDATION ___________________________________ 48 9 PATIENT SCREENING _______________________________________ 49 10 STUDY MONITORING, AUDITING AND INSPECTIONS _________ 49 10.1 STUDY MONITORING ____________________________________________ 49 10.1.1 GENERAL AIM OF MONITORING ___________________________________ 49 10.1.2 SOURCE DATA AND SOURCE DOCUMENTS ___________________________ 50 10.1.3 CASE REPORT FORM ____________________________________________ 51 10.2 AUDITS AND INSPECTIONS________________________________________ 51 11 CLINICAL STUDY REPORT, PUBLICATION, AND PATENT

PROTECTION _______________________________________________ 52 12 REGULATORY AND ETHICAL ASPECTS ______________________ 52 12.1 GENERAL REQUIREMENTS________________________________________ 52 12.2 ETHICS BASICS ________________________________________________ 53 12.3 PATIENT INFORMATION SHEET AND INFORMED CONSENT FORM___________ 53 12.4 PATIENT CARDS _______________________________________________ 55 12.5 LEGAL INSURANCE REQUIREMENTS ________________________________ 55 12.6 QUALIFICATIONS OF THE INVESTIGATORS ____________________________ 55 12.7 DATA PROTECTION _____________________________________________ 55 12.8 REGULATORY AUTHORITIES ______________________________________ 56 12.9 ESSENTIAL DOCUMENTS _________________________________________ 56 12.10 DISCONTINUATION OF THE STUDY__________________________________ 56 13 STUDY PROTOCOL, AMENDMENTS, DOCUMENTATION AND

ARCHIVING ________________________________________________ 57 13.1 STUDY PROTOCOL AND AMENDMENTS ______________________________ 57 13.2 DOCUMENTATION ______________________________________________ 58 13.3 ARCHIVING ___________________________________________________ 58 14 LITERATURE _______________________________________________ 60 15 AGREEMENT TO STUDY PROTOCOL_________________________ 63 15.1 SIGNATURES OF THE SPONSOR _____________________________________ 63 15.2 SIGNATURES OF EXTERNAL PARTIES ________________________________ 64 15.3 SIGNATURES OF THE INVESTIGATOR(S) ______________________________ 65 Appendix 1: Patient Information Sheet and Informed Consent Form 66 Appendix 2: Laboratory Parameters and Vital Signs Alert Limits 77


LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS AE Adverse Event AMG Arzneimittelgesetz (German Drug Law) ATP Adenosintriphosphate CK Creatine Kinase CRF Case Report Form CRO Contract Research Organization CSR Clinical Study Report e.g. Exampli gratia, for example NERD Non-Erosive Gastroesophageal Reflux Disease GCP Good Clinical Practice GERD Gastroesophageal Reflux Disease GMP Good Manufacturing Practice γ-GT Gamma Glutamyl Transferase ß-HCG ß-Human Chorion Gonadotropin HCL Hydrochloric acid H. pylori Helicobacter pylori i.e. Id est, that is ICH International Conference on Harmonization IEC Independent Ethics Committee IRB Institutional Review Board ITT Intention-to-Treat LA Los Angeles LDH Lactate Dehydrogenase LOC Local Operating Company MedDRA Medical Dictionary for Regulatory Activities MCV Mean Corpuscular Volume NSAIDs Non-steroidal anti-inflammatory drugs o.d. Once daily PP Per Protocol PPI Proton Pump Inhibitor SAE Serious Adverse Event SAP Statistical Analysis Plan


SGOT Serum Glutamate-Oxalacetate Transaminase = Aspartate Aminotransferase (ASAT) SGPT Serum Glutamate-Pyruvate Transaminase = Alanine Aminotransferase

(ALAT) SPC Summary of Product Characteristics SRMO Sponsor’s Responsible Medical Officer, i.e., sponsor’s responsible medical expert ULNR Upper Limit Normal Range VAS Visual Analogue Scale WBC White Blood Cell General arrangement for this study protocol: In the following text the terms patient and investigator are used for both, male and female, hereafter referred to as he.


LIST OF ADDRESSES Sponsor ALTANA Pharma AG Byk-Gulden-Strasse 2 78467 Konstanz Germany Sponsors Responsible Medical Renate Fischer, M.D. Officer (SRMO) see Sponsor Phone: +49(0)7531 / 84-2236 Fax: +49(0)7531 / 84-9 2236 Drug Safety Gerd Kassel, M.D., Ph.D. see Sponsor (Headquarter) Phone: +49 (0)7531 / 84-2297 (or 2242) Fax: +49 (0)7531 / 84-3000 Email:[email protected] Local Study Manager Sabine Weitzmann see Sponsor Phone: +49 (0)7531 / 84-2105 Fax: +49 (0)7531 / 84-92105 Biometrics Frank Grieger See Contract Research Organization Phone: +49 (0)201 / 8990 0 Fax: +49 (0)201 / 8990 101 Biometric Advisor Waldemar Braun see Contract Research Organization


Contract Research Organization IFE Europe GmbH Institute for Research and Development Z. Katharina 6 45307 Essen Germany Phone: +49 (0)201 / 8990 0 Fax: +49 (0)201 / 8990 101 Email: [email protected] Central Laboratory S. Spranger und Partner Ärzte für Laboratoriumsmedizin Lindbergh Str. 9-13 85051 Ingolstadt Germany Phone: +49 (0) 841 / 973 920 Fax. +49 (0) 841 / 973 929 [email protected] Supervising Investigator Prof. Dr. Joachim Mössner ‘Leiter der Klinischen Prüfung’ Universitätsklinikum Leipzig according to German Drug Law Liebigstr. 20 (§4, §40 AMG) 4103 Leipzig Germany

Phone: +49(0) 341 / 97109


1 SUMMARY Indication Symptomatic non-erosive reflux disease (NERD) or erosive

gastroesophageal reflux disease (GERD) Phase III Study centers Approximately 35 centers in Germany Objective of the study This is the first study to prove fast symptom reduction in

hospitalized patients suffering from NERD or GERD after 1 day of treatment with pantoprazole 20 mg (NERD) or with pantoprazole 40 mg (GERD A-D).

Study design Open, multicenter, stratified (GERD/NERD) Number of patients 350 patients in 35 study centers intention to treat (ITT), 285

patients per protocol (PP) Patient population Hospitalized patients of at least 18 years of age with

endoscopically confirmed NERD or GERD grade A to D according to Los Angeles (LA) classification

Study medication Pantoprazole (tablet) 40 mg (GERD A-D )/20 mg (NERD),

oral administration Duration of study April 2006 – July 2007 (first patient in – last patient out) Study period per patient NERD: 7 days treatment with pantoprazole 20 mg GERD A-D: 7 days treatment with pantoprazole 40 mg Primary variable(s) Symptom reduction from reflux disease related symptoms

measured as assessed by ReQuest™ GI after 1 day of treatment


Secondary variables • Symptom reduction from reflux disease related symptoms as

assessed by ReQuest™ -GI after 2, 3, 4, 5, 6, 7 days of treatment

• Symptom relief rates as assessed by ReQuest™ after 7 days of treatment

• Symptom relief rates as assessed by ReQuest™ after 7 days of treatment for patients suffering from each classification of reflux disease (NERD and GERD LA classification A-D) at baseline

• Time to reach first relief from reflux disease related symptoms for the ReQuest™ total score and the subscale ReQuest™ GI

• Relief rates from reflux disease related complaints after 7 days of treatment (as assessed by the investigator)

• Influence of the H. pylori-status on the symptom relief rates as assessed by ReQuest™

• Influence of concomitant diseases on the symptom reduction • Influence of concomitant diseases on the measurement error • Safety

For the secondary variables, separate analyses will be done for the subgroups ‘NERD’ and ‘GERD’ and regarding concomitant medication, for the subgroups ‘intake of NASIDs’ and ‘no intake of NSAIDs’. Statistical methods Primary analysis based on the ITT population is the

reduction of symptoms from baseline to day 1. The according difference of the ReQuest™ GI scores will be tested two-sided by the one sample t-test on an α-level of 5%.

In addition, for the primary and the secondary variable separate analysis will be done for the subgroups NERD and GERD.


Course of the study (A) NERD Pantoprazole 20 mg

350 ITT patients (B) GERD A-D Pantoprazole 40 mg Treatment Period: 7 days (+/- 3 days) Schedule of Visits Day 0 Day 7 (+/- 3 days) Baseline Visit (V0) Final Visit (V1)


2 INTRODUCTION

2.1 The Investigational Product Pantoprazole

Pantoprazole was synthesized in the laboratories of Byk Gulden (now renamed ALTANA Pharma) and, from a chemical point of view, belongs like Omeprazole and Lansoprazole to the group of substituted benzimidazoles. Pantoprazole is an acid-activated H+/K+-ATPase inhibitor in the acid secretory parietal cells of the stomach mucus membrane. Through the pharmacological mode of action of ATPase inhibition a strong, long-lasting and selective inhibition of gastric acid secretion, comparable to that of omeprazole, is reached (Simon et al., 1990; Hartmann et al., 1992). The principle of acid inhibition with pantoprazole leads, in diseases that show an etiological relationship with acid secretion such as peptic ulcer and NERD and GERD, to favorable therapeutic results. In contrast to other available inhibitors of acid secretion, such as H2-receptor antagonists and antimuscarinics, H+/K+-ATPase inhibitors work on the common last step in the effect chain of HCl secretion and lead to a stimulus-type independent acid inhibition. Pantoprazole is a weak base that is protonated in the canalicular compartment of parietal cells. The protonated form is converted to a cyclic sulphenamide, the active substance. This binds covalently to thiol groups and leads to a long-lasting inhibition of the H+/K+-ATPase (Shin et al., 1993). Acid secretion is reactivated, among other means, by the de novo synthesis of the membrane bound enzyme. The complete activation of pantoprazole only takes place under the strong acidic conditions of the canalicular compartment of the parietal cells. By protonation of the starting material, the back-transport through the parietal cells is also prevented. Due to this two-fold limitation of the effect on the proton pump of the parietal cells, adverse substance-specific effects are to a large extent avoided. Pantoprazole has a similar efficacy on acid secretion inhibition in humans as other PPIs. Under neutral pH conditions, pantoprazole has a high chemical stability. The potential of pantoprazole to interact with the hepatic cytochrome P450-dependent oxidase system is low according to pre-clinical results as well as in trials with healthy subjects (Simon et al., 1991). In all clinical studies pantoprazole was well tolerated. Adverse events


rarely appeared, and mostly with mild to moderate intensity. A summary of the properties and licensed indications as well as all adverse drug reactions of pantoprazole is presented in the current valid Investigator’s Brochure and in the current valid national summary of product characteristics (SPC). The investigator receives both documents prior to study start.

2.2 The Comparator Product

Not applicable

2.3 Background of the Clinical Study

Gastroesophageal reflux disease (GERD) is one of the most common medical disorders, with estimates of up to 50% of adults reporting heartburn at least once per month and 4-7% experiencing typical symptoms daily (Johanson, 2000). However, there is often no correlation between the severity of reflux symptoms and mucosal damages observed by endoscopy (Dent et al., 1999). Possible complications of erosive esophagitis are ulcers, displacement by cylindrical epithelium (Barrett‘s esophagus), and strictures. In this context, the mucosa of the esophagus is damaged by aggressive gastric acid when natural protection mechanisms, such as the anti-reflux barrier (mainly the lower esophagus sphincter) and esophageal clearance mechanisms (esophageal peristalsis, gravity and others) do not function properly. The success of a medical therapy for GERD depends on the control of the gastric acid secretion (Bell et al., 1992). An increase of the gastric pH-value to ≥4 for at least 15 hours in a period of 24 hours leads to a healing rate of 90% in reflux esophagitis (Vaezi and Richter, 1997). ReQuest™ is a reliable, validated tool to measure symptoms in NERD and GERD patients. Until now no data are available in hospitalized patients. This is the first study to prove fast symptom reduction in these patients suffering from NERD or GERD after 1 day of treatment with pantoprazole 20 mg (NERD) or with pantoprazole 40 mg (GERD). It is expected that the majority of the patients are hospitalized due to other diseases. This gives the unique chance to study the influence of these diseases on the symptom reduction and the measurement error of the ReQuest™.


2.4 Risk / Benefit Consideration

Proton pump inhibitors such as pantoprazole are the treatment of choice in patients with acid-related diseases. Pantoprazole has proven to be a highly potent drug for healing and symptom relief in GERD patients in acute and maintenance therapy (Bardhan, 1999). Furthermore, pantoprazole has shown superiority with regard to efficacy to H2-receptor antagonists and placebo (Dammann and Kleist, 1997). In general, pantoprazole is a well-known proton pump inhibitor and very well tolerated.

3 STUDY OBJECTIVE The objective of the present study is to prove symptom reduction in hosptalized patients suffering from NERD or GERD after 1 day of treatment with pantoprazole 20 mg (NERD) or with pantoprazole 40 mg (GERD).

3.1 Primary Variable

The primary variable of this study is the symptom reduction from reflux disease related symptoms measured as assessed by ReQuest™ -GI after 1 day of treatment.

3.2 Secondary Variables

For description of the secondary variables please refer to Section 8.11. (Biometry).


4 STUDY DESIGN AND PATIENT POPULATION

4.1 Study Design

For this study an open, multicenter and stratified design is used.

4.2 Study Duration

The duration of the study for each patient comprises 7 days (+/- 3 days). The investigator will decide on further appropriate treatment of the reflux disease after study termination.

4.3 Patient Population

Approximately 350 ITT patients will be included into the study in order to obtain data from 285 PP patients. A maximum of up to 10 inpatients at each investigational site who have to be at least 18 years of age with symptomatic (heartburn, acid regurgitation or dysphagia for at least 1 day since admission to the hospital) non-erosive reflux disease (NERD) or erosive gastroesophageal reflux disease (GERD, LA grade A-D) will be included. It is mandatory that the included patients are hospitalized at the study start and during the entire study period. Approximately 35 investigational sites will participate in this study in Germany.

4.4 Inclusion Criteria

Written informed consent by the patient for study participation, prior to protocol specific procedures

Inpatients of at least 18 years of age (hospitalization during the entire study period is mandatory)

Symptomatic (heartburn, acid regurgitation or dysphagia for at least 1 day since admission to the hospital) non-erosive reflux disease (NERD) or erosive gastroesophageal reflux disease (GERD, LA grade A-D)


4.5 Exclusion Criteria

Signs, indicating other gastrointestinal diseases

Known Zollinger-Ellison syndrome or other gastric hypersecretory condition

Previous acid-lowering surgery or other surgery of the esophagus and/or upper gastrointestinal tract (exception: polypectomy and cholecystectomy)

On initial endoscopy, presence of obstructive esophageal strictures, Schatzki’s ring, esophageal diverticula, esophageal varices, achalasia or Barrett‘s esophagus with known high-grade dysplasia or longer than 3 cm

Acute peptic ulcer and/or ulcer complications

Pyloric stenosis

Known inflammatory bowel diseases

Other concomitant diseases

Severe or unstable cardiovascular (e.g. severe angina pectoris, postmyocardial infarction and ventricular extrasystoles), pulmonary, or endocrine disease; clinically significant renal or hepatic disease or dysfunction; hematologic disorder; any other clinically significant medical condition that could increase the risk to the study participant as considered by the investigator

Malignant disease of any kind during the previous 5 years except for successfully treated skin (basal or squamous cell) cancer

Tendency to react allergically to drugs, especially with known hypersensitivity to one of the compounds of the study medication

Alcohol, drug or medication abuse within the past year

Abnormal laboratory parameters and vital signs considered as clinically relevant by the investigator and not explainable by medical history

Severe psychiatric or neurologic disorders as considered by the investigator


Special restrictions for female patients

Pregnant or nursing female patients

Female patients of childbearing potential, who are not using and not willing to use medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, unless they are surgically sterilized / hysterectomized or any other criteria considered sufficiently reliable by the investigator in individual case

Previous medication

Proton pump inhibitors (PPIs) during the last 3 days before intake of study medication

H2-receptor antagonists or prokinetics : stop at Visit V0

Sucralfate, bismuth preparations or other substances, which may have an influence on the relief of acid-related symptoms: stop at Visit V0

Any medication for the purpose of the eradication of H. pylori during the last 28 days before intake of study medication

Concomitant medication

Proton pump inhibitors (PPIs, except study medication), H2-receptor antagonists, antacids, prokinetics, sucralfate, bismuth preparations or other substances, which may have an influence on the relief of acid-related symptoms

Onset or change in the first two days of the study of systemic glucocorticoids or non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2-inhibitors

Ketoconazole or other drugs with pH-dependent absorption

Proton pump inhibitors (PPIs) in combination with antibiotics for the purpose of the eradication of H. pylori


Others

Patients who are expected to be non-compliant and/or not co-operative

Participation in a clinical study within the last 30 days prior to the start of the study

Patients who have participated already in this study

Patients who are employees at the investigational site, relative or spouse of the investigator

Any donation of germ cells, blood, organs, or bone marrow during the course of the study

Patients who are not contractually capable

4.6 Interim Exclusion Criteria

Not applicable

4.7 Discontinuation Criteria

In general, the study will be discontinued for individual patients in the case of unwillingness to continue or lack of efficacy. Lack of efficacy is defined as the continuation with the same intensity/frequency or deterioration of symptoms, which according to the investigator’s assessment require further investigation. Furthermore, patients should be withdrawn from the study if in the investigator’s opinion it would be to the patients’ detriment to continue. In addition, pregnant patients have to be immediately withdrawn from the study.


5 STUDY MEDICATION, DOSAGE AND STORAGE

5.1 General

The sponsor will provide an adequate amount of study medication together with the appropriate release statement approving the study medication for human use in this clinical trial. All medication supplied by the sponsor to be used in this study will be manufactured, tested and released according to current legal requirements and Good Manufacturing Practice (GMP). The supplied medication are tablets containing either:

A - pantoprazole 20 mg (NERD)

B - pantoprazole 40 mg (GERD)

The entire study medication for 7 days will be packed in a patient package with a blister (containing 15 tablets). The patient package and the blister were labeled according to national requirements.

5.2 Labeling of Study Medication

The study medication is labeled according to national legal requirements. All required information is given in German language. A tear-off label is attached to each patient package. This tear-off label is self-adhesive and the investigator is required to remove the tear-off part and attach it to the corresponding section of the Case Report Form (CRF) when the study medication is dispensed to the patient.

5.3 Storage

No special storage conditions are required. The investigator is responsible for handling and storing the study medication safely and properly at the investigational site in a locked facility, with access limited to the investigator and authorized personnel. The


investigator is responsible for ensuring that the study medication is administered in accordance with the study protocol and only to patients enrolled in the study.

5.4 Dosage Regimen and Intake

Based on the result of the endoscopy, the patients are assigned to one of the following treatment groups: Group A (NERD) pantoprazole 20 mg o.d. Group B (GERD A-D) pantoprazole 40 mg o.d. The patient has to take orally 1 tablet pantoprazole (20 or 40 mg) one hour before breakfast. Tablets should not be chewed or crushed and have to be swallowed whole with water. The study medication has to be stored in the original and closed bottles.

5.5 Start of Treatment and Instruction of Patients

Treatment starts on the day of the baseline (V0) visit on day 0. The date of first administration of the study medication has to be documented in the corresponding section in the CRF. On the following 7 days, 1 tablet per day will be taken with some water 1 hour before breakfast. The investigator has to inform the patient in detail how and when the medication has to be taken and that the patient should adhere to those instructions as close as possible. Furthermore, the patient should know that the package of pantoprazole is not empty if the instructions for the intake are strictly followed. Each patient should also be advised to return remaining study medication and all packaging.


5.6 Blinding

As this is an open study, no blinding procedures are necessary.

5.7 Randomization and Emergency Cards

As this is an open study, no randomization procedure is necessary.

5.8 Accountability of Study Medication

It is crucial for a therapeutic success that the patient takes his study medication regularly. The investigator has to check the compliance of the patient by counting the returned study medication at the final visit (V1). A patient is defined as compliant with regard to medication intake if he took no less than 80% and not more than 120% of the study medication scheduled for the corresponding interval of time (7 days +/-3 days). The investigator or authorized staff is obliged to document the receipt, distribution and return of all medication supplies including all study-related materials received during the course of this study. This includes detailed counting of the returned study medication on separate accountability forms. In addition, delegates of the sponsor have to check the returned study medication. Any difference in the documentation of the investigator and delegates of the sponsor must be clarified and corrected. The original study medication accountability forms are to be returned to the sponsor, the investigator retains a copy thereof. Any remaining study medication has to be returned to the sponsor who is responsible for the destruction. The sponsor files the respective destruction documents.


5.9 Supportive and Concomitant Medication

Known side effects and potential interaction of pantoprazole with other substances are listed in the current valid Investigator’s Brochure and corresponding summary of product characteristics (national current valid version).

5.10 Non-permitted Medication

Medications, which are not permitted prior and during the study are described in Section 4.5.

5.11 Permitted Medication

Concomitant medication is only permitted if it is indispensable due to intercurrent acute or chronic diseases or conditions. Full details of any medication administered (trade name, dosage regimen) have to be recorded in the relevant section of the CRF. The dose of concomitant medication required for a chronic disease should be kept as constant as possible throughout the study. Any change in concomitant medication during the course of the study as well as onset of new medication in accordance with the exclusion criteria has to be recorded by the investigator in the relevant section of the CRF. Note: Any newly occurred disease or condition and/or a deterioration of a current disease or condition has to be documented in section AE of the CRF. Symptoms and their intensity that are documented in the patient diary (ReQuestTM) will not be considered as AE. This does not apply if a cause other than the underlying disease is suspected.


5.12 Overdose

There are no known symptoms of overdosage of pantoprazole in man. Doses of up to 240 mg i.v. administered over 2 minutes were well tolerated. In case of an overdose with clinical signs of intoxication, the usual rules of intoxication therapy apply.


6 Methods and conduct of the study

6.1 Study Schedule

The following table summarizes visit dates, procedures and tests to be performed at each visit.

Examination

V 0

(Baseline)

V1

(Final visit)

Days 0 7

Accepted deviation ± 3days Patient information sheet and informed consent procedure

X

Inclusion and exclusion criteria X

Demographic data / Medical history X

Physical examination X

Vital signs X X

Concomitant disease / medication X X

Endoscopy* X

Symptomatology assessed by the investigator X X

Laboratory tests X

Pregnancy test for female patients of childbearing potential

X (urine + blood)

X (urine)

Urinalysis (dipsticks) X

H. pylori status: Serology X

Distribution of study medication X

Return of study medication / Compliance check

X

Adverse event assessment X

Diary ReQuestTM (short version) To be filled by the patient daily

* Endoscopy accepted within 7 days before first administration of study medication, diagnosis must be given according to the LA classification.


6.2 Methods

6.2.1 Patient Information Sheet and Informed Consent Procedure

Every investigator must obtain written informed consent from the patient prior to the patient‘s participation in the study (i.e., before any study specific procedures are carried out). The informed consent form must be personally dated and signed in duplicate by both the investigator and patient (please refer to Section 12.3). By dating and signing the informed consent form, the patient fulfills all in- and exclusion criteria and is admitted to the study and a CRF must be filled in. Each CRF has a pre-printed 5-digit number.

6.2.2 Medical History and Physical Examination

On admission to the study, the medical history, and demographic and anthropometric data have to be documented. Data of the medical history including details of previous and concomitant disease and/or medication have to be assessed, a physical examination has to be conducted and vital signs (blood pressure and pulse/heart rate, seated position after 30 min. rest; alert limits of laboratory parameters and vital signs are presented in Appendix 2) have to be measured. All data have to be recorded as further specified in the CRF.

6.2.3 Endoscopy

The endoscopy must have been performed due to the patients health status (no study specific procedure) by an experienced endoscopist. An endoscopy with the diagnosis NERD or GERD (LA classification A-D) must be available at the baseline visit (V0). Endoscopies performed prior to inclusion into the study will be acceptable, provided that they were done 7 days before intake of the first study medication.


The term NERD should be reserved for individuals who satisfy the definition of GERD, but who do not have either Barrett‘s esophagus or definite endoscopic esophageal mucosal breaks (esophageal mucosal erosion or ulceration) (Dent et al., 1999). Mucosal breaks are a clear indication of the presence of GERD, but so-called ‘minor changes‘ (erythema, edema, friability) are not (Bytzer et al., 1993). The grade of reflux esophagitis will be determined according to the Los Angeles (LA) classification (see Section 6.2.4). Patients classified as LA classification A – D are eligible for entry into this study. Endoscopies in which the grade of reflux esophagitis was determined according to a different classification system, e.g., based on Savary/Miller classification, have to be re-classified in the Los Angeles classification. The re-classification has to be documented in the patient file.


6.2.4 Grades of Reflux Esophagitis According to Los Angeles (LA) Classification

In this study the grades of reflux esophagitis have to be assessed according to the LA classification (Armstrong et al., 1996, Lundell et al., 1999). The definition of mucosal breaks was revised at the Genval Workshop 1997, published by Dent et al., 1999, resulting in the following definition of mucosal breaks: esophageal mucosal erosion or ulceration. Mucosal breaks are a clear indication of the presence of esophagitis, but so-called ‘minor changes’ (erythema, edema, friability) are not (Bytzer et al., 1993). Grade A: One or more mucosal breaks no longer than 5 mm, none of which extends between the tops of two mucosal folds.

Grade B: One or more mucosal breaks more than 5 mm long, none of which extends between the tops of the two mucosal folds.


Grade C: Mucosal breaks that extend between the tops of two or more mucosal folds, but which involve less than 75% of the esophageal circumference.

Grade D: Mucosal breaks which involve at least 75% of the esophageal circumference.

6.2.5 Symptom Assessment

6.2.5.1 Symptom Assessment by the Investigator

In addition to the ReQuest™, the patients will be questioned by the investigator regarding the following symptoms, which are reported in patients with GERD or NERD: heartburn (defined as a burning feeling, rising from the stomach or lower part of the chest up towards the neck), acid regurgitation, dysphagia, and epigastric pain/discomfort, at visit 0 (V0) and visit 1 (V1) regarding the last 3 days of treatment in the study.


The intensity of the symptoms is defined as follows: None: no symptoms Mild: hardly noticeable, negligible impairment of well-being Moderate: marked discomfort, but tolerable without immediate relief Severe: overwhelming discomfort, urgent desire for immediate relief

6.2.5.2 Symptom Assessment by the Patient

Reflux Questionnaire (ReQuest™) ReQuest™ is a patient-orientated self-assessment scale designed to assess the course of symptoms in patients suffering from NERD and GERD. ReQuest™ has proven psychometric properties, i.e. valid, reliable and highly responsive, in GERD (Bardhan et al., 2004A, Mönnikes et al., 2004) and NERD patients (Bardhan et al., 2004B), and is therefore acceptable as primary outcome measure for clinical studies that are designed to assess the effect of treatment on the spectrum of NERD and GERD symptoms (Stanghellini et al., 2004, Armstrong et al., 2004). ReQuest™ comprises a long as well as a short diary version, each covering 6 dimensions of GERD (acid complaints, upper abdominal/stomach complaints, lower abdominal/digestive complaints, nausea, sleep disturbances, and other complaints) with respect to the intensity and frequency of occurrence. Intensity is measured as degree of restriction by means of a 100 mm VAS ranging from ‘not at all’ to ‘extremely severe’. Frequency is measured by means of a 7-point Likert scale ranging from ‘0’ to ‘more than 10 times per day’ or ‘continuously’.


Furthermore, both long and short versions of ReQuest™ include a questioning about patient’s general well being measured by means of a 100 mm VAS ranging from ‘wonderful’ to ‘extremely poor’. In addition, the long versions of ReQuest™ cover symptoms, symptom descriptions, and complaints known to be typical for the respective dimension. During the validation studies it could be shown that short and long version are content valid. Therefore, both versions can be used separately in clinical studies. Within this study only the short ReQuest™ version will be used. ReQuest™ covers specific gastrointestinal symptom descriptions, and aspects affecting well-being. These can be grouped into two ReQuest™ subscales, i.e., ReQuest™ -GI (gastrointestinal: including acid complaints, upper abdominal/stomach complaints, lower abdominal/digestive complaints and nausea) and ReQuest™-WSO (encompassing general well-being, sleep disturbances and other complaints). Both subscales of ReQuest™ fulfill as well all requirements to be acceptable as a primary outcome measure for clinical studies that are designed to assess the effect of treatment on the spectrum of NERD and GERD symptoms (Bardhan et al., 2004A, Mönnikes et al., 2004, Bardhan et al., 2004B, Stanghellini et al., 2004). Before giving the ReQuest™ to the patient, both patient and investigational site personnel have the opportunity to get used to this tool by means of a sample card, which gives detailed instructions on how to complete the ReQuest™. In addition, a patient manual and an investigator manual will be provided to give detailed instructions and to allow all participants to become familiar with this tool. The ReQuest™ has to be supplied at V0 and should continuously be completed by the patient on a daily basis (day 0 – day 7). It is of utmost importance that the patient completes the ReQuest™ without help. The first entry into the Request questionnaire by the patient has to be given prior to the first medication intake assessing the symptoms during the last 24 hours.


Each ReQuest™ has a pre-printed number. At inclusion into the study the investigator has to document this number in the designated data array in the CRF. The patient number is identical to the pre-printed ReQuest™ number.

6.2.5.3 Information Flow

The investigator is instructed to send the ReQuest™ cards anonymously in prepaid and preaddressed envelopes to the data management (IFE Europe) directly after the patient has completed the study. The data management controls the availability of the diary cards regularly by means of a database. If the data management does not receive the diary cards after the scheduled time or if the data are incomplete, the data management will contact the investigational site. To improve the compliance of the ReQuest™ use, the investigational site reminds the patient during the course of the study to complete the diary cards regularly.

6.2.6 Laboratory Tests

6.2.6.1 Blood Samples

The central laboratory provides the investigational sites with the appropriate material prior to study start.


Blood samples (approximately 15 - 20 ml) have to be collected from each patient for determination of the following parameters at the baseline visit (V0):

Hematology Clinical Chemistry

Erythrocytes Alkaline Phosphatase ß-HCG (females)

Hematocrit Calcium H. pylori serology

Hemoglobin Cholesterol

Leucocytes (if abnormal, differential WBC)

CK (if > 3 x ULNR: CK-MB)

MCV Creatinine

Platelets Glucose

γ-GT

LDH

Potassium

SGOT (ASAT)

SGPT (ALAT)

Sodium

Total Bilirubin (if increased, direct and indirect Bilirubin)

Triglycerides

Urea

Uric acid

All blood samples have to be collected, prepared, and arranged for transport according to the instructions provided by the central laboratory. The investigator will receive the laboratory report by fax. This fax has to be copied and both sheets have to be dated and signed by the investigator. One sheet has to be filed


together with the original page of the CRF. The second sheet has to be filed together with the investigator’s copies of the CRF. As a general rule, no comments have to be given on the laboratory reports. In doubt of the reliability of laboratory results, an immediate re-investigation of the laboratory parameters is recommended. The central laboratory informs the investigator directly by telephone or by fax. At baseline (V0), deviations of laboratory values from the reference ranges considered as clinically relevant by the investigator and all values beyond alert limits (please refer to Appendix 2: Laboratory Parameters and Vital Signs Alert Limits) have to be documented in section ‘Medical History’ of the CRF as diagnosis of the patient( not the abnormal lab value only).

6.2.6.2 Pregnancy Test

If the female patient is of childbearing potential she must have a negative pregnancy test before the first intake of any protocol defined medicinal product. The blood pregnancy test is part of routine laboratory examination and has to be carried out at the initial visit (V0) (blood sampling). Additionally an urine pregnancy test has to be carried out at V0. If the study medication is handed out/administered before the result of the blood pregnancy test is available the result of the urine pregnancy test must be negative. Furthermore, at the final visit (V1) a further urine pregnancy test has to be carried out.

6.2.6.3 Urinalysis

The following parameters have to be determined: glucose, protein, and blood. The urinalysis (dipsticks) should be performed at the investigational site according to the manufacturer‘s instruction. In case of clinically relevant findings of unknown cause it is in the investigator’s discretion to decide on further measurements. The dipsticks are provided together with the laboratory material. The results have to be documented in the corresponding section of the CRF.


6.2.6.4 Determination of Helicobacter pylori Status

The H. pylori status will be determined by H. pylori serology at the central laboratory (cf. Section 6.2.6.1).

6.3 Conduct of the study

6.3.1 Baseline Visit (V0)

Patient information sheet and informed consent procedure Inclusion and exclusion criteria (Endoscopy result must be available,

NERD/GERD symptoms must be present) Demographic data, medical history, physical examination including

measurement of vital signs Concomitant disease and/or medication Endoscopy to determine NERD or grade of reflux esophagitis according to the

LA Classification must be available (to be documented into the CRF) Symptomatology assessed by the investigator Laboratory tests including blood pregnancy test for female patients of

childbearing potential Urine pregnancy test for female patients of childbearing potential Urinalysis (dipstick) H. pylori status: serology Diary ReQuest™ Distribution of study medication

6.3.2 Final Visit (V1)

V1 has to be performed 7 days after V0. A maximum deviation of +/- 3 days is permitted.

Changes in concomitant disease and/or medication Adverse event assessment


Vital signs Symptomatology assessed by the investigator Urine pregnancy test for female patients of childbearing potential Return of study medication / compliance check Return of Diary ReQuest™

6.3.5 Unscheduled Visits

Not applicable

6.3.6 Premature Termination from the Study

The patient may withdraw from the study at any time without giving reasons and without any disadvantageous consequences for his subsequent medical care. Furthermore, the patient should be withdrawn from the study if the investigator has the impression that it would be to the patient‘s detriment to continue. In case of premature withdrawal from the study the investigator should perform the following:

Changes in concomitant disease and/or medication Adverse event assessment Vital signs Symptomatology assessed by the investigator Urine pregnancy test for female patients of childbearing potential Return of study medication / compliance check Return of Diary ReQuest™


7 ADVERSE EVENTS

7.1 Definition and Documentation

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject, which does not necessarily have a causal relationship with any medical treatment. This definition includes any unfavorable and unintended signs, symptoms or findings, which newly appear or deteriorate during the clinical study, i.e., it includes all intercurrent illnesses (newly diagnosed concomitant diseases or symptoms) and clinically relevant deterioration in the clinical laboratory tests. Alert values of vital signs or clinical parameters that must be classified as clinically significant are defined in Appendix 2. Furthermore, this definition covers the entire study period independent of whether study medication is administered or not, with the following exception: untoward medical findings that occur prior to the administration of any study medication are not considered to be AE, if they occur in the scope of investigations that are performed to check inclusion or exclusion criteria (e.g., results of laboratory tests that are taken at the entrance examination). AE have to be recorded over the entire study period, i.e., the period of time from the first (written informed consent) to the last protocol-specific procedure. Symptoms and their intensity that are asked for and documented by the investigator in the CRF at each visit including patient diaries (ReQuest™) will not be considered as AE, except if a cause other than the underlying disease is suspected. The following principles apply to change in laboratory values. Laboratory alert limits are defined by upper or lower limits of parameters. All laboratory values beyond these limits are considered possibly clinically significant. The investigator should ensure that each parameter out of the normal range is assessed for clinical significance. Surgery and other invasive procedures that are planned prior to the start of the study do not have to be documented as AE. Planned procedures have to be recorded by the investigator in the CRF at V0. In this context, it should be noted that surgery is usually


not an AE but rather a measure to treat the AE. Therefore, a precise description of the medical event shall be given. The patient has to be instructed to inform the investigator immediately about all adverse events during the whole study period. The adverse events have to be documented in the CRF together with their intensity (mild, moderate or severe, refer to Section 6.2.5.1). Any AE, which is in accordance to the above definition, has to be documented by the investigator, regardless of any consideration on causality. The investigator can assign the cause of the AE to the intake of the study medication, or to another reason. The decision must be explained separately for each event. The investigator‘s final judgment on the causal relationship between the study medication and the AE event is based on the following scale: No relation There is an evident other explanation for the AE, e.g., - the AE is obviously explained by the patient‘s disease(s) or- the AE is in accordance with the effect or adverse effect of a concomitant

medication or- the AE has occurred already prior to administration of the study medication in

comparable intensity and/or frequency or - the AE started before first intake of study medication Unlikely relation There is a reasonable temporal relation between the AE and the intake of the study medication, but there is a plausible other explanation for the occurrence of the AE. Likely relation There is a reasonable temporal relation between the AE and the intake of the study medication, and plausible reasons point to causal relation with the study medication.


Definite relation - Reasonable temporal relation between the AE and the intake of the study

medication and - there is no other explanation for the AE and - subsidence or disappearance of the AE on withdrawal of the study medication

(dechallenge) and - recurrence of the symptoms on restart at previous dose. If the AE leads to a premature discontinuation of the study, the appropriate pages of the CRF must be completed. The documentation required at premature discontinuation is described in Section 6.3.6.

7.2 Serious Adverse Events

Any event shall be classified as serious that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, and any other medically important condition, which may jeopardize the patient or may require intervention to prevent one of the other outcomes listed above. This should also usually be considered serious. Concerning the serious criterion ‘death‘, it should be obeyed that death itself is not an adverse event, but rather the outcome of an event, which should be described using medical terminology. ‘Life-threatening‘ refers to an event, in which the patient was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death if it were more severe. ‘Hospitalization‘ is defined as inpatient care that covers more than one calendar day, even if the duration of hospitalization should be shorter than 24 hours. Note: This study will be carried out exclusively with hospitalized patients, therefore hospitalization will not be considered a serious adverse event.


Should a serious adverse event (SAE) occur, the investigator must contact the Drug Safety of the sponsor immediately by sending the completed appropriate form (serious adverse event reporting form) via fax/e-mail. Drug Safety: ALTANA Pharma AG Corporate Drug Safety / Pharmacovigilance Responsible Phone: +49 (0)7531 / 84 2242 Fax: +49 (0)7531 / 84 3000 Email: [email protected] ALTANA Pharma Corporate Drug Safety informs the Sponsor’s Responsible Medical Officer (SRMO) immediately of any serious adverse event. Important additional data on the SAE obtained later should be sent in the same manner on a follow-up form. An instruction how to complete and submit the SAE reporting form will be provided to the investigator by the sponsor at the start of the study. The SRMO is obliged to arrange a decision about premature termination of the study, if there is an increase in the risk/benefit ratio, e.g., should numerous SAE occur, that prove to have a likely or definite causal relation to the intake of the study medication. Ethic committees, supervising authorities, and investigators will be informed immediately by the sponsor in case of the discontinuation of the study for any reason or if new information is available that influences the risk/benefit ratio.

7.3 Notification of the Independent Ethics Committee / Institutional Review Board and the Health Authorities

The relevant IECs/IRBs and the health authorities will be notified of all safety aspects according to national law. The investigator is obliged to report AE to the authorities according to national legal requirements. In order to avoid duplicate reports, the sponsor is responsible for this


compulsory registration. A condition thereof, however, is that the investigator has completely and correctly recorded all AE in the CRF including exact posology (dosage, form, strength, daily dose, regimen), route of administration, starting and stopping date of treatment, information on concomitant treatment, description of AE/suspected adverse reaction, preferably diagnosis, date of onset of AE, duration, seriousness, outcome, dechallenge/rechallenge information, and causality assessment of reporter.

7.4 Follow-up of Adverse Events

The AE shall be followed by the investigator until its resolution or until the AE is recognized as permanent condition. If an AE persists at the end of the regular study course and the investigator is not able to provide a final outcome, it is at the discretion of the responsible Drug Safety Physician if the AE has to be followed by the investigator until its resolution or until the AE will be recognized as permanent condition. In any case of any laboratory value or vital sign being beyond the alert limit at the end of the study, a follow-up laboratory investigation as well as measurement of vital signs has to be performed and the final outcome to be documented on the corresponding AE page of the CRF by the investigator. Follow-up is not required if a deviation from the laboratory alert limits was already present prior to the administration of study medication as well as in case of:

• Abnormal laboratory parameters caused by mechanical or physical influences on the blood sample (e.g., hemolysis) and marked as such by the laboratory on the laboratory report

• Abnormal parameters that are obviously biological implausible (e.g., values, which are incompatible with life).

However, follow-up investigations may be necessary according to the investigator‘s medical judgment, even if the patient has no AE at the end of the study. In this situation, the follow-up does not have to be documented in the CRF but must be noted in the source documentation.


7.5 Follow-up of Serious Adverse Events

In cases SAE persist or newly occur at the end of the regular study period, the course of events has to be followed by the investigator until its resolution or until the SAE will be recognized as permanent condition. As a general rule the SAE follow-up period should be 30 days. SAEs, which are reported by investigators within 30 days after study termination, will be documented and assessed by Corporate Drug Safety as if they had occurred during the study period.

7.6 Pregnancy

If pregnancy is suspected during this study, study medication must be immediately withheld until the result of a laboratory pregnancy test is available. Should pregnancy be confirmed, the patient must be withdrawn from the study. Patients should be instructed to notify their investigators in case they become pregnant either during the study or within 30 days after the treatment period. A pregnancy should be followed to term, any premature terminations reported, and the status of the mother and child reported to ALTANA Pharma after delivery via the Pregnancy Questionnaire. ALTANA Pharma Corporate Drug Safety must be notified within one working day after the day, the investigational site becomes aware of the pregnancy. ALTANA Pharma Corporate Drug Safety will contact the attending physician during the patient’s pregnancy after the estimated date of delivery to enquire about course and outcome of the pregnancy and to request the documentation on the Pregnancy Initial and Follow-up Questionnaires. Pregnancy per se does not classify as an adverse event. However, adverse events related to a pregnancy have to be reported like any other adverse events. Pregnancies must be reported via telephone to the Drug Safety of the sponsor (for address refer to 7.2), immediately after the investigator‘s knowledge of pregnancy.


ALTANA Pharma Corporate Drug Safety informs the Sponsor’s Responsible medical Officer (SRMO) immediately of any pregnancy. The pregnant patient should sign her consent to be obtained by the investigator for purpose of informing the sponsor of the outcome of her pregnancy. Completion of the Pregnancy Initial Questionnaire is required by the investigator and must be faxed to the Drug Safety (for address refer to 7.2). The sponsor provides these questionnaires, if applicable. Pregnancies have to be documented in the investigator’s file, in the patient‘s source documents and on the study termination page of the CRF.


8 BIOSTATISTICAL METHODS 8.1 General

This chapter describes the statistical analysis as it is foreseen at the time of planning the study. Any major deviations from this plan, the reasons for such deviations, and all alternative or additional statistical analyses that may be performed will be mentioned in the Statistical Analysis Plan (SAP), which gives a detailed technical description of all statistical analyses prior to the final lock of the clinical database. All deviations and/or alterations will be summarized in the clinical study report (CSR).

Because of the unpredictability of potential problems, it may be necessary to decide about the manner of dealing with irregularities in a review meeting.

8.2 Stating the Problem

This open, multicenter, stratified study represents the first evaluation to prove symptom reduction in hospitalized patients suffering from NERD or GERD (LA grade A – D) within a 7 day treatment period with pantoprazole 20 mg (NERD) or with pantoprazole 40 mg (GERD A-D).

8.3 Study Design

This study will be performed with an open, multicenter and stratified design.

8.4 Analysis Sets and Types of Analyses

Analyses will be based on the following sets: total set, safety set, full analysis set, and per protocol set. The definitions of the analysis sets follow those given in the ICH E9 guideline (1998).

8.4.1 Analysis Sets

8.4.1.1 Total Set

The total set consists of all patients enrolled including non eligible patients.


8.4.1.2 Full Analysis Set

The full analysis set is used to describe the analysis set which is as complete as possible and as close as possible to the intention-to-treat set including all enrolled patients. Exclusion from the full analysis set is limited to the following reasons:

• Failure to satisfy major entry criteria (details see ICH E9 guideline): Hospitalized patients of at least 18 years of age with endoscopically confirmed NERD or GERD grade A to D according to Los Angeles (LA) classification

• Failure to take at least one dose of study medication.

An exclusion from the full analysis set will be justified in the CSR. The intention-to-treat (ITT) analysis is based on this data set. 8.4.1.3 Per Protocol Set

The per protocol set, sometimes described as valid cases set, includes all patients who are compliant with the study protocol. Also patients who terminated the study prematurely because of an event related to the study medication are included in the valid cases set (per definitionem: premature termination of the patient’s study participation because of an adverse event, that was classified by the investigator as at least ‘likely related’ with the study medication or premature termination of the patient’s study participation due to lack of efficacy). The per protocol analysis is based on this data set.

The following patients will be classified as protocol violators and excluded from the valid cases set:

- Patients whose findings at V0 later indicate a possible severe disease

- Patients who have deviated considerably from the study protocol (e.g., poor compliance, deviations from or not attending to the scheduled visit and violations of inclusion/exclusion criteria).


- Premature termination of the patient’s study participation due to adverse events, which in the investigator’s causality assessments are either ‘not related’ or ‘unlikely related’ to the intake of study medication.

- Premature termination of the patient’s study participation for reasons, which are not causally related to intake of the study medication.

8.4.1.4 Safety Set

The safety set includes all enrolled patients for whom it cannot be ruled out that they took the study medication at least once.

8.4.2 Type of Analysis

Patients will be analyzed according to the treatment the patient was assigned to. The primary population for analysis will be the ITT population.

8.4.2.1 Intention-to-Treat (ITT) Analysis

The ITT analysis will be based on the full analysis set. 8.4.2.2 Per Protocol (PP) Analysis

The PP analysis will be based on the PP set. 8.4.2.3 Analysis of Safety

The safety analysis will be based on the safety set. 8.5 Primary, Co-primary and Key-secondary Variable(s)

The primary variable of this study is the symptom reduction from reflux disease related symptoms measured as assessed by ReQuest™- GI after 1 day of treatment.


8.6 Testing Procedure

The difference of the ReQuest™- GI scores (baseline, day 1) will be tested two-sided by the one sample t-test on an α-level of 5%. 8.7 Statistical Analysis of Primary Variable, Co-primary and Key-

secondary Variable(s) and Statistical Hypothesis

Primary analysis based on the ITT population is the reduction of Request-GI symptoms from baseline to day 1. The respective difference of the ReQuest™ GI scores will be tested two-sided by the one sample t-test on an α-level of 5%. For the primary variable a separate analysis will be done for the subgroups NERD and GERD. 8.8 Interim Analysis

An interim analysis is not planned. 8.9 Sample Size Considerations

Baseline values of ReQuest™ -GI are approximately 5 score points and a reduction of 10% within one day should be shown in this study. A standard deviation of 3 score points results in 285 patients based on the two sided t-test and α=0.05 and a power of 80%. Taking protocol violators into account 350 patients should be included into the study. 8.10 Randomization

Not applicable. 8.11 Secondary Variables and their Statistical Analyses

• Symptom reduction from reflux disease related symptoms as

assessed by ReQuest™ -GI after 2, 3, 4, 5, 6 and 7 days of treatment will be analyzed analogous to the primary variable.


• The symptom relief rates as assessed by ReQuest™ after 7 days of treatment and the respective 95% confidence intervals will be calculated.

• The symptom relief rates as assessed by ReQuest™ after 7 days of treatment for patients suffering from each classification of reflux disease (NERD and GERD LA classification A-D) at baseline and the respective 95% confidence intervals will be calculated.

• The time to reach first relief from reflux disease related symptoms for the ReQuest™ total score and the subscale ReQuest™ GI will be analyzed using survival methods.

• The relief rates from reflux disease related complaints after 7 days of treatment (as assessed by the investigator) and the respective 95% confidence intervals will be calculated.

• To analyze the influence of the H.pylori-status on the symptom relief rates as assessed by ReQuest™, these symptom relief rates and the respective 95% confidence intervals will be calculated for H.pylori-positive and H.pylori-negative patients at baseline separately.

• The influence of concomitant diseases on the symptom reduction will be analyzed.

• The influence of concomitant diseases on the measurement error will be analyzed.

For the secondary variables separate analyses will be done for the subgroups ‘NERD’ and ‘GERD’ and regarding concomitant medication, for the subgroups ‘intake of NASID’ and ‘no intake of NSAID’. 8.12 Subgroup Analyses

Analyses for the subgroups NERD and GERD and ‘intake of NASID’ and ‘no intake of NSAID’ will be done.


8.13 Clinical Laboratory

Clinical laboratory data will be presented on an individual basis and will be marked according to the normal ranges provided by the selected central laboratory and corresponding sponsor guidelines, respectively. Descriptive summary statistics will be presented for each variable. In addition, the number of patients with values outside the normal range and extended normal ranges will be presented.

8.14 Adverse Events

The recorded adverse events will be coded according to MedDRA V5.1. The adverse events will be summarized by treatment, System Organ Class, preferred-term and intensity.

Nature, incidence and intensity, as well as the investigator's and the sponsor's causality assessment will be reported for each treatment-emergent adverse event. Descriptive summary statistics, e.g. with regard to the incidence of symptoms and the causality assessment, will be presented for the treatment period (V0 – V1, 7 days).

8.15 Health Economics and Health Related Quality of Life

Not applicable.

8.16 Handling of Missing Values

Missing values within the ReQuest™ questionnaire will be handled according to the evaluation manual for the ReQuest™ version 2.0. 8.17 Data Entry and Validation

Data management procedures will be specified in the data management plan.


9 PATIENT SCREENING ICH E6, 8.3.20 and ICH E3, 10.1 require documentation of the patient screening. Patients screened for inclusion irrespective whether they are included or not have to be documented on the screening log provided by the sponsor. The reasons for non-inclusion will then be classified and the frequency of classes is evaluated. A comparison between the patient population included in the study and the screening population will help to clarify the appropriate patient population for eventual drug use. The screening is finished as soon as an investigational site has no further study medication left or when the sponsor terminates the study because the planned patient number has been reached.

10 STUDY MONITORING, AUDITING AND INSPECTIONS

10.1 Study Monitoring

10.1.1 General Aim of Monitoring

The general aim of monitoring is to ensure that the quality of work performed by the investigator in the clinical study complies with the study protocol and with the requirements of national and local authorities. Authorized, qualified delegates of the sponsor have to contact the investigational sites at regular intervals, usually every 4 to 6 weeks (i.e., prior to the study start - pre-trial monitoring visit, at the start of the study – study initiation monitoring visit, throughout the study - monitoring visits and at the end of the study - final trial close-out visit). In addition, the delegates of the sponsor should contact the investigational site at an early stage. Furthermore, in case of non-recruitment the investigational site should be contacted to discuss the problems. The visits of the authorized delegates provide an opportunity for both the investigator and the sponsor to discuss individual questions that may arise in the course of the study and to facilitate the investigator‘s task to maintain a complete and consistent CRF and


patient file. If the investigator has any questions with respect to the study in the time between the visits he is asked to discuss them in detail by contacting the delegates of the sponsor or the respective local sponsor or CRO (please refer to list of addresses).

10.1.2 Source Data and Source Documents

Source data are all information in original records and certified copies of original records of clinical findings, observations, or other activities in the clinical study necessary for the reconstruction and evaluation of the study data (e.g., progress notes, hospital records, computer print-outs, screening logs and recorded data from automated instruments). Entries in the ReQuestTM diary as well as symptoms as assessed by the investigator in the CRF symptom are also regarded as source data and do not have to be recorded in the patient file. In case of computerized source data it is required for the investigator to have an audit trail system or to provide printouts of the patient file at each monitoring visit. Those printouts have to be dated and signed by both the investigator and the delegates of the sponsor. It is mandatory that the investigator keeps source data of each patient in the patient‘s file. Database print-outs of the ReQuest™ data will be sent to the investigator in a timely manner and have to be filed in the investigator's file together with the CRF data of the respective patient. To ensure data quality, the authorities require in accordance with the data protection regulations and guidelines a source data verification between the CRF and the source documents obtained. For this purpose, the investigator consents to allow the delegates of the sponsor or auditor(s) direct access to the source documents related to the study with keeping of confidentiality.


10.1.3 Case Report Form

Each CRF page consists of 1 original page and 2 copy pages. The language used in the CRF is English. After consistency and plausibility check as well as completion of each CRF including source data verification, the delegate of the sponsor forwards the original pages of the CRF for data entry to the responsible data management department. In addition, one copy page has to be filed in the investigator‘s file and the other copy page has to be filed in the local study file (if applicable). Queries are resolved by using query sheets. Without obscuring the original data, the corrections have to be entered by the investigator or delegates according to the signature sheet, and dated and signed by the investigator. The delegate of the sponsor files a copy of the query sheet in the investigator‘s file and in the local study file (if applicable). The original query sheet has to be returned to the responsible data management department for data entry and processing.

10.2 Audits and Inspections

In order to ensure adherence to the guidelines, authorities, delegates of the sponsor as well as other authorized persons are permitted to conduct an audit or an inspection. By dating and signing this study protocol the investigator consents to a possible audit and/or inspection, to give his full cooperation and to allow direct access to all relevant source documents and other study-related data.


11 CLINICAL STUDY REPORT, PUBLICATION, AND PATENT PROTECTION

The results of the clinical study have to be documented by the sponsor in a clinical study report. The SRMO and the coordinating investigator declare their consent with the clinical study report with their signature. As this is a multicenter study, the results will only be published when the study is clinically completed at all investigational sites and data evaluation is done. The sponsor has to be provided with all manuscripts/abstracts at least 4 weeks prior to submission for publication. This does not involve any restrictions regarding content with the reservation of any restrictions made for patent protection reasons. The sponsor has no responsibility for any consequences arising from the publication as long as he is not a co-author. No study-related information may be passed on from the investigator or other personnel involved in the clinical study to external parties, without prior written consent of the sponsor. The sponsor retains all patent rights regarding pantoprazole.

12 REGULATORY AND ETHICAL ASPECTS Please refer to: ICH Harmonized Tripartite Guideline E6 — Guideline for Good Clinical Practice, May 1996.

12.1 General Requirements

By signing and dating this protocol the investigator acknowledges receipt of detailed information concerning prior pharmacological/toxicological studies via the Investigator‘s Brochure. This clinical study is carried out in accordance with the Declaration of Helsinki, taking into account the revised versions of Tokyo 1975, Venice 1983, Hong Kong 1989, and


Somerset West 1996, the EC directive on data protection and on the basis of applicable national laws in each participating country. In addition, the guidelines for Good Clinical Practice of the International Conference on Harmonization will be followed as long as they do not violate national laws.

12.2 Ethics Basics

Prior to the start of the clinical study the sponsor or investigator must submit all documents, which are required according to national laws and regulations to the competent IEC/IRB. In general, the local sponsor of the participating country carries out this task or supports the investigator in the submission procedure. The start of the clinical study is only allowed after the study protocol is approved in writing by IEC/IRB. All ethics votes and assessments to each participating investigational site have to be kept at the sponsor. The approval and site-specific correspondence or at least a copy thereof has to be filed at the investigational site.

12.3 Patient Information Sheet and Informed Consent Form

Every investigator must obtain written informed consent from each patient prior to the start of any study-related measures (e.g., first intake of study medication and/or any tests/investigations/examinations). For this purpose, patients must be informed verbally and in writing by the investigator about the nature, significance, implications and risks of the study prior to enrollment. All items must be explained by the investigator in a language and in terms that are easy to understand for the patient. It is highly recommended that the investigator documents short notes about the content and course of the informed consent procedure (e.g., in the patient file). Full details must be given to the patient including the type and methods of the clinical study, tests to be performed, any potential or proven hazards, risks/benefits of the study-specific and alternative treatments. The patient should also be counseled on recommended measures to support the process of symptom reduction (please refer to Appendix 1 ‘Patient Information Sheet and Informed Consent Form‘).


The investigator has to inform the patient that his consent to participation can be withdrawn at any time, without giving any reason, and that no disadvantages will result regarding further medical treatment. The refusal of a patient to participate in a study must never interfere with the investigator-patient relationship. The investigator shall ask for the reason of premature termination without violating the patient‘s rights (ICH-E6 4.3.4). Furthermore, the patient must be informed about the insurance coverage provided by the sponsor and required by law, as well as his corresponding obligations (please refer to Appendix 1 ‘Patient Information Sheet and Informed Consent Form‘). All information is summarized in the patient information sheet, which the investigator has to provide to the patient. The informed consent form must be personally dated and signed in duplicate by both the patient and the investigator. The patient receives one original version of the informed consent form and the second original of the informed consent form is to be filed in the investigator‘s file. Furthermore, the investigator confirms the patient‘s consent in the CRF. By signing the informed consent form, the patient also declares his agreement to the provision of direct access to his patient file and to the passing on of his study-related data in pseudonymous form to the sponsor, the relevant national and local regulatory authorities and the IEC/IRB, in accordance with the EC directive on data protection and the national data protection regulations, respectively. It is recommended that the investigator informs the patient‘s primary physician about the patient‘s participation in the study, if the patient has a primary physician and if the patient agrees to the primary physician being informed.


12.4 Patient Cards

After having given his written informed consent to participate in the clinical study, each hospitalized patient receives a patient card, which indicates the patient number, the study drug and the address of the sponsor. In emergency cases, this provides essential information for an adequate reaction of not involved stuff at the study site.

12.5 Legal Insurance Requirements

Insurance coverage exists in line with the legal requirements. Before the start of the clinical study, the investigator has to inform the patient of the insurance provided by the sponsor. The investigator has to point out that throughout the study, except in cases of emergency, the patient must not receive additional medication or other treatment from another physician without prior approval of the investigator. The patient should also be aware that in case of an adverse event the investigator has to be contacted immediately.

12.6 Qualifications of the Investigators

The sponsor is obliged to obtain evidence of the investigator‘s qualification to perform the clinical study. Therefore, the investigator has to provide a dated and signed copy of his professional curriculum vitae (no older than 2 years and preferable one page in English) prior to the start of the clinical study including information about his experience in conducting clinical studies according to the guidelines for Good Clinical Practice.

12.7 Data Protection

For data protection reasons, the investigator has to disclose the identity of the patients involved in this study only in a pseudonymous form. This does not apply in case of an emergency, where a disclosure may be necessary to avoid health risks.


12.8 Regulatory Authorities

The sponsor is obliged to inform the competent regulatory authorities of the complete and accurate data obtained in the course of the study. For this reason, the investigator has to provide the sponsor with all observations and results as outlined in the study protocol and CRF. The relevant local and federal authorities are informed by the sponsor about the clinical study performance and may observe the study progress. The study protocol together with the investigators‘ names, the investigational sites and the approval of the ethic committees are presented to the Health Authorities of the participating countries, if applicable.

12.9 Essential Documents

Before the start of the clinical study all documents according to the guideline for Good Clinical Practice (ICH E6 8.f) and other necessary documents including the financial disclosure form as required by authorities must be available in the files at the sponsor and the investigator where required. The investigator‘s file given to the investigator prior to the start of the clinical study contains all essential documents including the guideline for Good Clinical Practice of the International Conference on Harmonization, the Declaration of Helsinki (amended version Somerset West 1996) and special requirements as specified by national and local law.

12.10 Discontinuation of the Study

The sponsor may terminate the study for safety, ethical or administrative reasons at any time. In such cases, all investigators have to be notified in writing, outlining the reasons for the termination.


In particular cases, the study may be terminated at a single investigational site, if the sponsor has relevant reasons, e.g., suspicion of a deceit or conduct of the study, which is not in accordance with the guidelines for Good Clinical Practice. It is at the discretion and responsibility of the investigator to decide in individual cases on the patient‘s withdrawal from the study due to medical reasons. Furthermore, the patient can withdraw from the study at any time, without giving any reason.

13 STUDY PROTOCOL, AMENDMENTS, DOCUMENTATION AND ARCHIVING

13.1 Study Protocol and Amendments

The investigators as well as the authorized qualified delegates of the sponsor have to consent to the study protocol by giving their personally dated signatures. Supplements and/or changes have to be appended to the study protocol as amendments. Each amendment has to be signed by at least the SRMO, the international study manager and investigator, if applicable. The SRMO and international study manager decide on additional signatures to be obtained depending on the contents of the amendment and the persons/departments concerned. The decision has to be documented in writing. Substantial amendments likely to affect the safety of the patients or the conduct of the study have to be submitted to all IECs/IRBs concerned. They should be asked for their opinion if a re-evaluation of the ethical aspects of the study appears to be called for. If in case of multicenter studies an IEC/IRB demands modifications of a study protocol/patient information sheet/informed consent form already approved by other IECs/IRBs it has to be decided by the sponsor case by case whether those changes shall be adopted only for the respective investigational site or all sites.


13.2 Documentation

The investigator receives one case report form (CRF) for each patient. After receipt of the written informed consent, the CRF has to be completed for all study-specific procedures with all relevant data for the duration of the clinical study in a complete and accurate manner. Data of patients who were screened for inclusion irrespective whether they are included or not have to be documented on the screening log provided by the sponsor (please refer to Section ‘Patient Screening‘). Entries in the CRF have to be verifiable by the source data in the patient file (either as print-outs or as notes taken by either the investigator or another responsible person assigned by the investigator on the signature sheet) with the exception of source data as defined in Section 10.1.2. Study participation of the patient including patient number must be clearly documented in the patient file. Use of a black ball pen is recommended to ensure clarity of copies of the CRF pages. All corrections in a CRF have to be made in a way that does not obscure the original entry. The corrected data have to be inserted with the reason for the correction, if necessary, dated and initialed by the investigator. As the ReQuest™ data are not part of the CRF the investigators will receive database print outs of the ReQuest™ data from the sponsor in a timely manner to file in the investigator's file.

13.3 Archiving

The investigators are responsible for the archiving of the data according to the national and international legal requirements (national law, EC Directive 2001/83/EC, ICH E6). According to those the investigators have to archive the investigator‘s file including the subject identification code list and enrollment log (patient number, full name, date of birth, sex, date of enrollment, site specific identification of the patient) and the signature sheet of all involved staff, who was authorized by the investigator to take over study related duties (names, signatures and initials, role and authorization), the patient‘s file as


well as the source data for at least 20 years or until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or if at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product, whatever is the longer period of time. However, these documents should be retained for a longer period if required by the applicable national regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to when these documents no longer need to be retained. If an investigator leaves an investigational site for whatever reason, the responsibility for all study related records have to be transferred to another person (e.g., other investigator, sponsor). The sponsor has to be informed about any change of responsibility in writing including the name of the new responsible party, contact information, and location of study documentation. Records may not be destroyed without prior written consent from the sponsor.


14 LITERATURE Armstrong D, Bennett JR, Blum AL; Dent J, De Dombal FT, Galmiche JP, Lundell L, Margulies M, Richter JE, Spechler SJ, Tytgat GNJ, Wallin L (1996): The endoscopic assessment of esophagitis: A progress report on observer agreement. Gastroenterology 111: 85-92 Armstrong D, Mönnikes H, Bardhan KD, Stanghellini V (2004): The construction of a new evaluative GERD questionnaire – Methods and state of the art –. Digestion 70: 71-78 Bardhan KD (1999): Pantoprazole: A new proton pump inhibitor in the management of upper gastrointestinal disease. Drugs of Today 35: 773-808 Bardhan KD, Stanghellini V, Armstrong D, Berghöfer P, Gatz G, Mönnikes H (2004A): Evaluation of GERD symptoms during therapy. Part I: Development of the new GERD questionnaire ReQuest™. Digestion 69: 229-237 Bardhan KD, Stanghellini V, Armstrong D, Berghöfer P, Gatz G, Mönnikes H (2004B): International validation of ReQuest™ in patients with endoscopy-negative gastro-oesophageal reflux disease. Aliment Pharmacol Ther 20: 891-898 Bell NJV, Burget D, Howden CW, Wilkinson J, Hunt RH (1992): Appropriate acid suppression for the management of gastroesophageal reflux disease. Digestion 51: 59-67 Bytzer P, Havelund T, Moller, Hansen J (1993): Interobserver variation in the endoscopic diagnosis of reflux esophagitis. Scan J Gastrenterol 28:119-25 Dammann HG, Kleist DH (1997): Efficacy and tolerability of pantoprazole versus ranitidine and famotidine in patients with gastroesophageal reflux disease: multi-center, open randomized, controlled studies. International Clinical Practice Series, Eds: Domschke W, Wells Medical Limited, Kent, UK: 23-29


Dent J, Brun J, Fendrick AM, Fennerty MB, Janssens J, Kahrilas PJ, Lauritsen K, Reynolds JC, Shaw M, Talley NJ on behalf of the Genval Workshop Group (1999): An evidence-based appraisal of reflux disease management - the Genval Workshop Report. Gut 44(2): S1-S16 Hartmann M, Theiß U, Bliesath H, Kuhn I, Lühmann R, Huber R, Wurst W, Postius S, Lücker P (1992): 24-h intragastric pH following oral intake of pantoprazole and omeprazole. Hellenic J Gastroenterol 5 (suppl 2): 113ff Johanson JF (2000): Epidemiology of esophageal and supraesophageal reflux injuries. Am J Med 108: 99-103 Lundell LR, Dent J, Bennett JR, Blum AL, Armstrong D, Galmiche JP, Johnson F, Hongo M, Richter JE, Spechler SJ, Tytgat GNJ, Wallin L (1999): Endoscopic assessment of esophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut 45: 172-180 Mönnikes H, Bardhan KD, Stanghellini V, Berghöfer P, Bethke TD, Armstrong D (2004): Evaluation of GERD symptoms during therapy. Part II: Psychometric evaluation and validation of the new GERD questionnaire ReQuest™. Digestion 69: 238-244 Shin JM, Besancon M, Simon A, Sachs G (1993): The site of action of pantoprazole in the gastric H+/K+-ATPase. Biochim Biophys Acta Bio Membr 1148: 223-233 Simon B, Müller P, Marinis E, Lühmann R, Huber R, Hartmann M, Wurst W (1990): Effect of repeated oral administration of BY1023/SK&F96022 - a new substituted benzimidazole derivative - on pentagastrin stimulated gastrin acid secretion and pharmacokinetics in man. Aliment Pharmacol Ther 4: 373-379 Simon WA, Büdingen C, Fahr S, Kinder B, Koske M (1991): The H+, K+-ATPase inhibitor pantoprazole (BY1023/SK&F96022) interacts less with cytochrome P 450 than omeprazole and lansoprazole. Biochem Pharmacol 42: 347-355


Stanghellini V, Armstrong D, Mönnikes H, Bardhan KD (2004): Systematic review: do we need a new gastro-oesophageal reflux disease questionnaire? Aliment Pharmacol Ther 19 (5): 463-479 Vaezi MF, Richter JE (1997): Gastroesophageal reflux disease. Current Opinion in Gastroenterology 13: 327-332


15 AGREEMENT TO STUDY PROTOCOL

15.1 Signatures of the sponsor

We hereby declare that the study entitled ‘Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg o.d. for 7 days’, study number BY1023/DE-004, will be conducted in accordance with the study protocol, the ‘Declaration of Helsinki‘ amended version Somerset West 1996, the international guidelines for Good Clinical Practice and any national and local laws and regulations. ALTANA Pharma AG (HEADQUARTER) Sponsor‘s Responsible Medical Officer Date:

(R. Fischer, M.D.)

Senior Local Study Manager Date:

(S. Weitzmann)


15.2 Signatures of external parties

We hereby declare that the study entitled ‘Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg o.d. for 7 days’, study number BY1023/DE-004, will be conducted in accordance with the study protocol, the ‘Declaration of Helsinki‘ amended version Somerset West 1996, the international guidelines for Good Clinical Practice and any national and local laws and regulations. Biometric Advisor Date:

(W. Braun)

Contract Research Organization Date:

(A. Beckerling, M.D.)

Supervising investigator acc. to §4, § 40 German Drug Law Date:

(J. Mössner, M.D.)


15.3 Signatures of the Investigator(s)

The undersigned investigator(s) agree(s) to the following: 1. The study ‘Symptom reduction in hospitalized patients suffering from

symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg o.d. for 7 days’‚ study number BY1023/DE-004 is performed by the undersigning investigator(s) in accordance with the study protocol, the Declaration of Helsinki amended version Somerset West 1996, the international guidelines for Good Clinical Practice and any national and local laws and regulations.

2. Alteration of the procedures described in the study protocol is not allowed without prior written approval from the sponsor.

3. The study-specific data of the patients are kept in the patient file and are documented in the case report form in a complete and accurate manner. Source data verification is performed by the authorized qualified delegates of the sponsor in accordance with the data protection regulations and the above-mentioned guidelines. For this purpose the investigator should make available all requested study-related records for direct access.

4. Authorized qualified delegates of the sponsor perform regular visits to ensure good quality data and to identify possible errors at an early stage.

5. Unused study medication and material are to be returned to the sponsor. 6. The investigator should ensure that all persons assisting with the clinical study are

adequately informed and trained about the study protocol, the investigational products and their study-related duties and functions.

7. The investigator should disclose his financial interests in the participation of the study.

Center ID:__________________ Investigator Date:

(Name in capital letters) (Signature) Sub-investigator Date:

(Name in capital letters) (Signature) Sub-investigator Date:

(Name in capital letters) (Signature)


Study Protocol BY1023/DE-004, Final Version 1.0, December 20, 2005 Page 66 of 77 Appendix 1: Core Version Patient Information Sheet and Informed Consent Form

Appendix 1: Patient Information Sheet and Informed Consent Form

Patient Information Sheet (core version)

Dear Patient,

According to your medical history you are eligible to participate in this clinical study. Clinical studies are necessary to gain and extend knowledge on the efficacy, safety and tolerability of drugs. It is a binding law that new drugs are clinically tested. The participation in a clinical study is entirely voluntary and therefore, it is necessary that you give your written consent prior to your participation by free will. Please, read the following information carefully. You will have ample time and opportunity to inquire about details of the study and to decide whether or not to participate in this clinical study. Your doctor is always ready to answer your questions and give you the explanations you need. Reading this information or asking questions does not imply any obligation to take part in this study. Please, give your consent to participate in this clinical study only if you have completely understood the nature and course of this study and if you are aware of your rights as a participant. You are fully entitled to revocate your consent any time and in this case no new data will be collected (i.e. all already collected data will be maintained in the database for further evaluation). Title of the clinical study Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg o.d. for 7 days. This study is organized and funded by the pharmaceutical company ALTANA Pharma AG and the local operating company Germany (LOC Germany):


ALTANA Pharma AG Byk-Gulden-Str. 2 D-78467 Konstanz, Germany Why is this study carried out? You belong to a large group of patients, who suffer from gastroesophageal reflux disease with (GERD) or without inflammation (NERD), which is caused by the reflux of aggressive acid from the stomach into the esophagus. The reflux may lead to an inflammation and/or may lead to acid-related complaints. This disease can be effectively treated with drugs, which inhibit acid production. The decrease in acid production will accelerate the healing of the esophageal inflammation and/or relieve your symptoms. The purpose of this study is to investigate your symptom relief during a treatment period of 7 days. What do you have to know about the study medication? In this study, you will be assigned to one of two possible study treatment groups, depending on the result of your endoscopy which has been performed already due to your gastrointestinal complaints. If your physician diagnoses you with an inflammation you will be allocated to the ‘GERD’ group, if no inflammation is present you will be allocated to the ‘NERD’ group. GERD: Gastroesophageal Reflux Disease NERD: Non-Erosive Gastroesophageal Reflux Disease Patients of the two treatment groups will be treated as follows:

1) GERD A-D: Pantoprazole 40 mg tablets 2) NERD: Pantoprazole 20 mg tablets


Pantoprazole is a drug which is approved for the treatment of gastroesophageal reflux disease and available worldwide. It is a highly effective drug that rapidly inhibits the production of gastric acid, so that a substantial relief of your complaints and/or a healing of your esophageal inflammation can be expected already after a short treatment period. At the baseline visit (V0) you will receive 1 package containing a blister with 15 pantoprazole tablets (20 or 40 mg). The first tablet should be taken at the baseline visit (V0). On the following 7 days, please take 1 tablet per day with some water 1 hour before breakfast. The tablets should not to be chewed or crushed and have to be swallowed whole. For a successful treatment, the exact and regular intake of the study medication is crucial. If you forget the intake of one tablet any day, please do not take the double dose the next day. The study medication has to be stored in the original packaging and out of reach of children and other persons who are not able to judge on the possible risks of drugs. For further storage instructions, please read the label of the study medication carefully. Please, return all unused study medication and all packaging to your physician at the final visit (V1). What other therapeutic alternatives do exist? Some general measures may also contribute to a reduced occurrence of complaints, e.g., elevating the head of your bed, avoiding late meals and others. Your study doctor will inform you about these measures. Currently, there are several other drugs, which also reduce the gastric acid production, on the market for treatment of gastroesophageal reflux disease. Your study doctor will inform you accordingly. Who should not participate in this clinical study? Pregnant and nursing female patients are not allowed to participate in this study. In case you become pregnant during the study period or within 30 days after discontinuation of


study medication or even in case you suspect to be pregnant, please immediately inform your doctor. If you are of childbearing potential you have to use a medically reliable method of contraception (e.g., pill, IUD) for the entire study duration. Please ask your doctor for further suitable methods of contraception. You must not have taken part in another clinical study 30 days prior to this study and you should not take part in another clinical study at the same time. How and where is this clinical study performed? This clinical study is carried out at several study sites (35 hospitals) in Germany with a total number of 350 participating patients. The study will take 7 days for each patient. Your doctor will inform you in detail about nature and significance of the clinical study. By signing the informed consent form, you agree to participate in the study. You will then receive a patient card containing the address and phone number of your doctor and of the sponsor of the study, as well as your patient number and the visit date for the final visit. You should carry this card with you during the entire study period in order to be able to reach your doctor or the sponsor in case of an emergency. With your agreement, your doctor is recommended to inform your family doctor (if you have one) about your participation in the study. A number of procedures will be conducted at each visit. The procedures may vary between visits and include

- Physical examinations, blood pressure and heart rate measurements. - Blood sampling (approximately 15-20 ml) from a vein in your arm for the

determination of routine laboratory parameters including H.pylori serology and collecting of a urine sample. The blood and urine samples will also be used to test for pregnancy if you are female and if it is possible for you to become pregnant. Different methods for the assessment of your complaints o Your doctor will ask for your present gastrointestinal (stomach) complaints .


o You will receive a patient diary (ReQuestTM) to document the frequency and intensity of complaints of your disease during the last 24 hours. Your doctor will support you in the regular completion by reminding you during the course of the study. Your doctor will explain the use of this diary in detail. It is essential for the result of this study that you complete the diary regularly on a daily basis, beginning with day V0 prior to the first drug intake.

The schedule which procedure is performed on which visit is displayed in the following chart: Examination Baseline Visit

(V0) Day 0

Final visit (V1)

Day 7 (+/-3 ) Physical examination X Blood pressure and heart rate measure-ments

X X

Blood sampling X Urine samples X X Pregnancy test X

(Urine + Blood) X

(Urine) Present complaints X X Patient Diary (ReQuestTM)

To be filled in daily by the patient

What has to be taken into account during the study? If you need additional medication, e.g., to treat a common cold, headache etc., please ask your doctor in all cases. The same applies when another physician prescribes you some medication. Exceptions are only allowed in case of an emergency. What are the possible risks of this clinical study? Like any other medication, the study drug (pantoprazole) can cause some unwanted effects:


Frequency Organ System

common (>1/100, < 1/10)

uncommon (>1/1,000, <1/100)

rare (<1/1,000,

>1/10,000)

Very rare (<1/10,000, incl. isolated reports)

Blood and lymphatic system

Leukopenia, Thrombocytopenia

Gastrointestinal disorders

Upper abdominal pain; Diarrhoea; Constipation; Flatulence

Nausea / Vomiting Dry mouth

General disorders and administration site conditions

Peripheral edema

Hepatobiliary disorders

Severe hepatocellular damage leading to jaundice with or without hepatic failure

Immune system disorders

Anaphylactic reactions in-cluding anaphylactic shock

Investigations Increased liver enzymes (transaminases, γ-GT); Elevated triglycerides; Increased body temperature

Musculoskeletal, connective tissue disorders

Arthralgia Myalgia

Nervous system disorders

Headache Dizziness; Disturbances in vision (blurred vision)

Psychiatric disorders Mental depression Renal and urinary disorders

Interstitial nephritis

Skin and sub-cutaneous tissue disorders

Allergic reactions such as pruritus and skin rash

Urticaria; Angioedema; Severe skin reactions such as Stevens-Johnson-Syndrome; Erythema multiforme; Photosensitivity; Lyell-Syndrome

For possible interactions of pantoprazole with other drugs and other interactions (e.g., with food ingredients) please ask your doctor. Generally, in rare cases it is possible that after intake of drugs allergic reactions (anaphylactic shock) of life threatening character occur.


Furthermore, the specific investigations carried out within the scope of this study, may cause complaints or bear some risks (e.g.allergic reactions). Blood sampling may cause pain, swelling, bruising or infection from the needle puncture sites. Please inform your study doctor about all symptoms, problems, illnesses or injuries, that you experience during and up to 30 days after the course of the study, within the scope of this study, such experiences are called ‘Adverse Events’ and have to be recorded in your personal study documents. Whenever these experiences are serious, please inform your doctor immediately. Please support your doctor as much as possible in the further clarification of any adverse event. Of course your doctor will give you the respective treatment according to your individual needs. In general, treatment or procedures conducted during the study may involve risks (including risks to unborn children), which are currently unforeseeable. What is the benefit from participating in this clinical study? Up to now, therapy with drugs that strongly inhibit the gastric acid production, like the medication used in this study, has shown best therapeutic effects and is currently the treatment of choice for your disease. It is expected from pantoprazole that you reach a high degree or even complete relief of your complaints after a short treatment period. In addition, you will have thorough examinations for your disease. You will get free medical examinations. You do not have to pay for your study medication. By taking part in this study, you help us to learn more about the treatment of gastroesophageal reflux disease. Will new scientific knowledge of the study medication be communicated? Whenever new scientific results on the study medication, which might influence your decision to participate in this study, become available, your doctor will inform you immediately. You have the right to decide either to continue with the study or to withdraw.


You are entitled to ask the doctor further questions regarding the study at any time. He will comment on any problem in detail and answer any occurring question in a comprehensible way. Is there an insurance coverage for the duration of the study? ALTANA Pharma and its representatives have provided insurance coverage in accordance with legal requirements for any injury or illness that is caused by your participation in the study. However, by signing the consent form you do not waive any legal rights, which you may have in the event of negligence or other wrong doing by anyone involved in the study. If it is suspected that your health has been damaged, the below-named company must been informed immediately, directly by yourself or by your study doctor. Gerling Konzern, Harvestehuder Weg 25, 20149 Hamburg, Germany Phone No: +49 (0)40 / 44199-0, Fax: +49 (0)40 / 44199-410 Insurance Policy No: 70-5201089-0 You are obliged to cooperate in the efforts to determine the cause or extent of any impairment, which may occur in relation to the study and to lessen the impairment. ALTANA Pharma and its representatives can provide further information on the conditions of the insurance coverage that has been taken out, if you wish. Who has approved the study? The study protocol and this patient information sheet were presented to an Independent Ethics Committee/Institutional Review Board and national authorities, whose members agreed to the performance of the clinical study as described. The study will be performed in accordance with national legal requirements. Is it possible to discontinue the study? Your participation in this clinical study is voluntary. You are fully entitled to withdraw from the study at any time without stating any reasons and without having any disadvantage to your further medical treatment.


If you withdraw from the study prematurely, it is advisable for your own safety to undergo the examinations that usually would take place at the end of the study, e.g. measurement of blood pressure and pulse rate. The objective of these examinations is to document the clinical status of all patients, who terminated the study prematurely. Should there, for whatever reason, exist any problem in the state of your health at the end or at the premature termination of the study, this will be followed until clarification. Your study doctor may also decide to remove you from the study if you fail to follow instructions, for medical reasons or for other reasons. There is also the possibility that the sponsor will stop either the whole clinical study or your participation in particular for safety reasons, only. Are the data treated confidential ? In addition to the usual medical files, further specific data are recorded in the scope of this clinical study. Those data are transmitted in pseudonymous form to the sponsor of this clinical study for scientific evaluation and subsequent report to national and international regulatory authorities and will be kept at the sponsor for at least 5 years after the end of market approval. Information of this study may be published, but your identity will be kept confidential in any publications. The correct documentation of the medical records and findings is necessary for the purpose of the research and serves to support the safety of the drug. You have the right to review your recorded data, which are collected in the scope of this clinical study, and to require any correction of any data that are wrong. Authorized personnel of the sponsor ALTANA Pharma and of the contract research organization IFE-Europe, the staff of competent local supervising authorities as well as the Independent Ethics Committees/Institutional Review Boards may examine your personal medical records. All persons, who are entrusted with this data verification, are obliged to maintain strict confidentiality and to follow the data protection laws.

A certified central laboratory will analyze blood samples collected in the scope of this clinical study. The blood samples will then be retained for 14 days and subsequently destroyed. However, if you revoke your consent to participate in this study you may require immediate destruction of all retained blood samples. Re-analyses or additional analyses are not planned. Authorized personnel of the central laboratory may examine your laboratory data. Who can be contacted for further questions? For further questions regarding this clinical study or your rights as patient and participant in the study, please contact your doctor, who will always be ready to provide you with the necessary information. If you have experienced any health-related problem as well as in case of hospitalization please contact your doctor. Name and address of Contact Person: Phone Number: Please take a copy of this information sheet with you. THANK YOU FOR READING THIS INFORMATION!


Informed Consent Form (core version) BY1023/DE-004

(EudraCT Nr. 2005-004856-11)

Symptom reduction in hospitalized patients suffering from symptomatic non-erosive or erosive gastroesophageal reflux disease treated with pantoprazole 20 or 40 mg o.d. for 7

days.

Full name of the patient (in block letters):

Date of birth: Patient number:

I freely agree to participate in the above-mentioned clinical study sponsored by ALTANA Pharma.

My doctor informed me in a personal counseling interview about the study drug, possible side effects and risks, the nature, objective and significance of this clinical study, the existing insurance as well as my responsibilities resulting thereof. In addition, I read and understood the contents of the Patient Information Sheet and the Informed Consent Form. The doctor answered all questions in an adequate and comprehensible manner. I had sufficient time to decide on my participation in this clinical study.

I will follow the instructions of my doctor, which are essential for the performance of this clinical study. I have the right to withdraw from the study at any time without giving any reason and without any disadvantage for me.

I agree that my personal data, in particular medical records that are collected in the scope of this clinical study, are marked with my date of birth, gender and race. These data will be

• recorded, stored either electronically or partly as paper version and evaluated • passed on to the sponsor and to associated national and international companies for

scientific evaluation and further scientific use • transmitted to the appropriate national and international regulatory authorities

Furthermore, I agree that authorized delegates of the sponsor or delegates of the aforementioned authorities or ethics committees may examine my personal data, i.e., the medical records with my personal particulars. This serves the complete and correct transfer of the data for the scientific evaluation and performance of the clinical study.

I confirm that I have not participated in this study and I have not taken part in another study within the last 30 days.

I received one original of the Patient Information Sheet together with the signed Informed Consent Form. (Place, date and signature of the patient)

(Place, date and signature of the doctor)


Appendix 2: Laboratory Parameters and Vital Signs Alert Limits

Parameter Criterion Chemistry

SGOT (ASAT) > 3x Upper Limit of Normal Range SGPT (ALAT) > 3x Upper Limit of Normal Range γ-GT > 3x Upper Limit of Normal Range Alkaline Phosphatase > 3x Upper Limit of Normal Range Creatinine > 2x Upper Limit of Normal Range Total Bilirubin > 2x Upper Limit of Normal Range CK > 3x Upper Limit of Normal Range Potassium > 6.0 mmol/L or < 3.0 mmol/L Sodium > 150 mmol/L or < 130 mmol/L Glucose > 2 x Upper Limit of Normal Range

Hematology

Hemoglobin Male < 11.5g/dL Female < 9.5g/dL

WBC Count < 2,800/mm3 or > 16,000/mm3

Eosinophiles > 20 %

Platelet Count < 75,000/mm3 or >700,000/mm3

Erythrocytes Male < 3,5 x 106/μL or > 7 x 106/μL Female < 3,0 x 106/μL or > 6.5 x 106/μL

Vital Signs

Blood pressure (BP): Systolic > 170 mmHg or < 85 mmHg Diastolic > 105 mmHg

Difference systolic BP at study termination (increase or decrease) compared to pre-treatment > 40 mmHg

Pulse/heart rate (resting): > 120 bpm or < 50 bpm Difference heart rate at study termination (increase or

decrease) compared to pre-treatment > 30 bpm

Study Protocol BY1023/DE-004, Final Version 1.0, December 20, 2005 Page 77 of 77 Appendix 2: Laboratory and Vital Signs Alert Limits