Rebamipide and Misoprostol: Multicenter RCT-STORM 149 Introduction Nonsteroidal anti-inflammatory drugs (NSAIDs) contribute to the management of arthritis and other inflammatory con- ditions. Upper gastrointestinal (GI) adverse events, ranging from dyspepsia to life-threatening complications such as perforation, are the primary side effects associated with NSAIDs. Gastroprotective agents are therefore often prescribed concomitantly with NSAIDs. Ulcers can be documented endoscopically in up to 40% of chronic NSAID users; however, it is estimated that as many as 85% of these ulcers never become clinically apparent [1]. Misoprostol and omeprazole, are only prescribed drugs in decreasing the NSAID-associated GI mucosal injury. Prophylaxis by gastroprotective agents decreases ulcer complications associated with long-term NSAID use. Misoprostol is a synthetic prostaglandin (PG) E1 analogue that has been shown to be gastroprotective by augmenting depleted mucosal defense factors and inhibiting gastric acid secretion. Numerous studies have been performed on the use of misoprostol to prevent NSAID-induced gastrointestinal complications. A dose–response study showed that 600 ug and 800 ug doses of misoprostol yielded similar protective effects [2]. Misoprostol reduces the risk of endoscopic ulcers, even at doses of 400, 600, and 800 µg/day [2–4]. However, a high incidence of diarrhea has been reported and documented in many patients on continuous misoprostol treatment. Rebamipide (2-(4-chlorobenzoylamino)-3-[2-(1H)-quinolinon- 4-yl]-propionic acid) (Otsuka Pharmaceutical Co., Tokyo) is a cytoprotective antiulcer drug that enhances defense mechanisms in the gastric mucosa by increasing gastric mucus and stimulating the production of endogenous prostaglandins, and has been reported to reduce gastric mucosal injury [5, 6]. The anti-inflammatory effects of rebamipide are due to its inhibitory effect on the production of superoxides [7]. Rebamipide significantly accelerated ulcer healing, in association with the expression of epidermal growth factor and epidermal growth factor receptor [8]. The efficacy of rebamipide in preventing NSAID-induced gastric injury has been reported in healthy volunteers on indomethacin treatment [9]. However, the efficacy of rebamipide in preventing NSAID-induced gastrointestinal complications has not been determined. The purpose of this study was to evaluate the cumulative incidence of NSAID- induced gastrointestinal complications such as ulcers in rebamipide- and misoprostol-treated groups in a random- ized, multicenter, controlled trial. Methods Vol. 40, No. 2, 2007 Study design A randomized, multicenter, controlled, open-label trial was performed in Korea, China, and Thailand. The subjects were recruited for treatment sequences in random fashion according to a randomization schedule for the treatment period from departments of rheumatology and internal medicine outpatient clinics. Individuals who were at least 18 years of age with rheumatoid arthritis, osteoarthritis, or ankylosing spondylitis or any other condition that required continuous NSAID therapy for more than 12 weeks were included in this study. Exclusion Criteria were as follows: individuals with a history of a serious medical condition (chronic liver disease or chronic renal disease); individuals with any other clinically significant gastrointestinal diseases confirmed by endoscopy, such as GERD, esophageal varix, peptic ulcer, or malignancy; those with a history of any documented gastric surgery or any malignant disease; those reporting recent use (within 4 weeks prior to the study) of sucralfate, H2-RA, misoprostol, PPIs, prokinetics, or any other medications that could affect acid secretion or gastro- intestinal motility; and those reporting recent use (within 4 weeks prior to the study) of any NSAIDs, corticosteroids, anticholinergics, antineoplastics, or anticoagulants. Patients were randomly assigned to receive either 100 mg rebamipide or 200 µg misoprostol t.i.d. for 12 weeks. Assessment of dyspepsia using a diary card and compliance with the trial drug and NSAIDs was performed every 2 weeks until 12 weeks (Fig. 1). Concomitant use of NSAIDs during this study was limited to aceclofenac, diclofenac, fenoprofen, ibuprofen, naproxen, and sulindac. Patients with a rate of compliance of less than 85% with study drugs and minimum daily dosage of NSAIDs were excluded from the study. The severity of dyspeptic symptoms was scored on a four-point scale. The study protocol was approved by the Ethics Committees of each of the 12 participating hospitals, and written informed consent was obtained from each of the patients. Randomization Subjects were recruited for the treatment sequences in random fashion according to a randomization schedule for the treatment period. A randomization number that was associated with a specific treatment with either rebamipide or misoprostol was assigned to each patient included in the study. The treatment was randomly assigned using an allocation ratio of 1:1 for the two treatment groups. Patients were allocated to the next available randomization number at each center. Allocation of randomized numbers was performed using the SAS program. Endoscopic evaluation Two endoscopists reviewed still images to establish standardized reporting criteria for ulcers and other lesions. At endoscopy, video or photographic images were recorded separately for the esophagus, gastric body, gastric antrum,