2018 Section 6 - Laryngology, Voice Disorders, and Bronchoesophalogy

S. E. Attwood et al.

SOPRAN study. The SOPRAN study was conducted between 1991 and 2005 in four Nordic countries (Den- mark, Finland, Norway and Sweden). Patients with chronic GERD (with re fl ux oesophagitis) were rando- mised to receive maintenance treatment with either PPI therapy (omeprazole 20 mg or 40 mg once daily) or sur- gery (open ARS). 8 The study period was initially 5 years, but was extended to 14 years. Data on all adverse events (nonserious and serious) were collected at baseline and at regular follow-up visits during the fi rst 5 years. After 5 years, only data on SAEs was collected. Laboratory variables were measured at baseline and at regular fol- low-up visits throughout the study (1, 3, 5, 7, 10 and 12 years). LOTUS study. The LOTUS study was conducted between 2001 and 2009 in eleven European countries (Belgium, Denmark, France, Germany, Austria, Iceland, Italy, Nor- way, Sweden, UK and The Netherlands). 9, 10 Patients with chronic GERD (with re fl ux oesophagitis and/or pathological pH-metry) were randomised to receive maintenance treatment with either PPI therapy (esomep- razole 20 mg once daily, adjusted to 40 mg once daily and then 20 mg twice daily if required) or surgery (lapa- roscopic ARS). Data on SAEs and laboratory variables were collected at baseline and at regular follow-up visits throughout the study (1, 3 and 5 years). Data on nonse- rious AEs were not collected. The study period was ini- tially 5 years and was extended once to 7 years. Laboratory variables Assessment of laboratory safety variables included hae- matology and clinical chemistry analyses. In both the studies, serum creatinine, aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), calcium (corrected for albumin), ferritin, folate, gastrin, haemoglobin and vitamin B 12 were assessed. In the LOTUS study, chromogranin A, homocysteine, total iron-binding capacity, vitamin D, iron and zinc levels were also measured. In the SOPRAN study, only gastrin was analysed at a central laboratory. In the LOTUS study, all blood sam- ples were sent to a central laboratory for analysis. Adverse events All SAEs, whether spontaneously reported or reported in response to a standardised question, were classi fi ed according to the Medical Dictionary for Regulatory Activ- ities (MedDRA), as were objective fi ndings and observa- tions. After discussions with regulatory authorities,

amendments were made to the protocols to ensure all ongoing and discontinued randomised patients were fol- lowed up speci fi cally for vital status (dead or alive) and cardiovascular events. Statistical presentation The safety population was de fi ned as all patients who took at least one dose of omeprazole/esomeprazole or received ARS and for whom data were available after treatment initiation. SAEs and laboratory variables were summarised using descriptive statistics. It was not our aim [and is not generally appropriate because of differing time frames, differing surgical techniques (open ARS vs. laparoscopic ARS) and differing drugs (omeprazole vs. esomeprazole)] to compare safety data between the SOP- RAN and LOTUS studies, hence all safety-related data were analysed and are presented separately for these studies. As a natural consequence of the exceptionally long study periods, many patients discontinued before the end of the SOPRAN (14 years) and LOTUS studies (7 years). To ensure enough data points were available at each time increment for a robust analysis, 12-year and 5-year cut-offs were applied to the SAE analysis sets for the SOPRAN and LOTUS studies respectively. For both laboratory analysis sets, a 5-year cut-off was applied. It should be noted that data patterns beyond these time points are still similar to those reported in this manu- script. In the SOPRAN study, ALP levels were standardised according to the upper limit of normal observed at each respective laboratory. This was not done for other labo- ratory measurements as no signi fi cant differences were observed in the normal limits across laboratories. Patient exposure time The median exposure time for patients in the SOPRAN SAE analysis set (12-year exposure cut-off) was 10 years for patients in the open ARS group and 12 years for those in the omeprazole group. The total exposure time was 1324 years for the open ARS group (post-surgery) and 1518 years for the omeprazole group (on PPI treat- ment). The total exposure time was, therefore, 15% longer among those treated with omeprazole than in those who had open ARS. The median exposure time for patients in the LOTUS SAE analysis set was 5 years for patients in the laparo- scopic ARS group and in the esomeprazole group. The RESULTS

Aliment Pharmacol Ther 2015; 41: 1162 – 1174 ª 2015 John Wiley & Sons Ltd

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