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Randomized, Double-Blind, Placebo-Controlled Trial of the 5-HT1A Receptor Antagonist AZD7371 Tartrate Monohydrate (Robalzotan Tartrate Monohydrate) in Patients With Irritable Bowel Syndrome

Drossman, Douglas A., M.D.1; Danilewitz, Mervyn, M.D.2; Næsdal, Jørgen, M.D., Ph.D.3; Hwang, Clara, M.Ap.Stat2; Adler, John, Ph.D.3; Silberg, Debra G., M.D., Ph.D.2

American Journal of Gastroenterology: October 2008 - Volume 103 - Issue 10 - p 2562–2569
ORIGINAL CONTRIBUTIONS: Functional GI Disorders
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OBJECTIVES To investigate the efficacy and safety of the 5-hydroxytrypamine 1A (5-HT1A) receptor antagonist AZD7371 tartrate monohydrate (robalzotan tartrate monohydrate), termed AZD7371 here, in patients with irritable bowel syndrome (IBS).

METHODS Patients meeting the Rome II criteria for IBS (N = 402) were randomized to treatment with AZD7371 20 mg or 5 mg or matching placebo tablets twice daily for 12 wk. The patients completed daily and weekly diary assessments, reporting abdominal discomfort or pain and description of bowel movements. They also completed validated symptom and quality-of-life questionnaires.

RESULTS Neither AZD7371 regimen was significantly more effective than placebo in providing adequate relief from IBS symptoms in at least 2 out of 4 wk per month over the 12 wk of treatment. There was also no significant difference between the treatment groups and placebo in the change in score in the validated symptom and quality-of-life questionnaires. Overall, 22.1% of patients experienced adverse events (AEs) attributed to the study medication: 44 of 133 (33.1%) in the 20 mg AZD7371 group, 27 of 131 (20.6%) in the 5 mg AZD7371 group, and 17 of 134 (12.7%) in the placebo group. Also, 31 of 57 (54%) of AEs leading to discontinuation were central nervous system-related. Hallucinations or hallucination-like AEs were reported by eight patients taking AZD7371, and by none of the patients in the placebo group. After these events led to discontinuation in six patients, the study was prematurely terminated.

CONCLUSIONS In view of the AE profile and lack of efficacy in IBS, the clinical development of AZD7371 has been stopped.

1Division of Gastroenterology and Hepatology, University of North Carolina Center for Functional GI and Motility Disorders, Chapel Hill, North Carolina; 2AstraZeneca R&D, Wilmington, Delaware; 3AstraZeneca R&D Mölndal, Mölndal, Sweden; 4Gastroenterology Section, Mercy Hospital of Philadelphia, Philadelphia, Pennsylvania

Reprint requests and correspondence: Douglas Drossman, M.D., Division of Gastroenterology and Hepatology, University of North Carolina Center for Functional GI and Motility Disorders, 4150 Bioinformatics Building CB#7080, Chapel Hill, NC 27599–7080.

CONFLICT OF INTEREST

Guarantor of the article: Mervyn Danilewitz, M.D.

Specific author contributions: Douglas A. Drossman was the primary investigator of one of the investigation sites and was involved in designing the study and developing the manuscript. Mervyn Danilewitz was involved in planning and conducting the study. Jørgen Næsdal was involved in planning and conducting the study, interpreting the results, and developing the manuscript. Clara Hwang was involved in planning the study, analyzing the data, and reviewing the manuscript. John Adler was involved in the planning, analysis, and interpretation of the study and in the reviewing of the manuscript. Debra G. Silberg was involved in planning and conducting the study, in analyzing the data, and in editing the manuscript.

Financial support: This study was sponsored by AstraZeneca R&D Mölndal, Sweden. AstraZeneca was involved in the study design and data collection, analysis, and interpretation. Writing assistance was provided by Dr. Catherine Henderson of Oxford PharmaGenesis Ltd., supported by AstraZeneca.

Potential competing interests: Mervyn Danilewitz, Jørgen Næsdal, Clara Hwang, John Adler, and Debra G. Silberg were employees of AstraZeneca at the time of the study. Douglas A. Drossman has no relevant competing interests.

Received January 23, 2008; accepted June 24, 2008.

© The American College of Gastroenterology 2008. All Rights Reserved.
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