Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial

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Abstract

Background

Adrenomedullin (AM) is a bioactive peptide having many pleiotropic effects, including mucosal healing and immunomodulation. AM has shown beneficial effects in rodent models and in preliminary study for patients with ulcerative colitis (UC). We performed a clinical trial to investigate the efficacy and safety of AM in patients with UC.

Methods

This was a multi-center, double-blind, placebo-controlled phase-2a trial evaluating 28 patients in Japan with steroid-resistant UC. Patients were randomly assigned to four groups and given an infusion of 5, 10, 15 ng/kg/min of AM or placebo for 8 h per day for 14 days. The primary endpoint was the change in Mayo scores at 2 weeks. Main secondary endpoints included the change in Mayo scores and the rate of clinical remission at 8 weeks, defined as a Mayo score 0.

Results

No differences in the primary or secondary endpoints were observed among the four groups at 2 weeks. Despite the insufficient tracking rate, the Mayo score at 8 weeks was only significantly decreased in the high-dose AM group (15 ng/kg/min) compared with the placebo group (− 9.3 ± 1.2 vs. − 3.0 ± 2.8, P = 0.035), with its rate of clinical remission at 8 weeks being significantly higher (3/3, 100% vs. 0/2, 0%, P = 0.025). We noted mild but no serious adverse events caused by the vasodilatory effect of AM.

Conclusions

In this double-blind randomized trial, we observed the complete remission at 8 weeks in patients with steroid-resistant UC receiving a high dose of AM.

Clinical trial registry

JAPIC clinical trials information; Japic CTI-205255 (200410115290). https://www.clinicaltrials.jp/cti-user/trial/Search.jsp.

Electronic supplementary material

The online version of this article (10.1007/s00535-020-01741-4) contains supplementary material, which is available to authorized users.

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Most cited references 29

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Infliximab for induction and maintenance therapy for ulcerative colitis.

Paul Rutgeerts, William J Sandborn, Brian Feagan … (2005)

Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor alpha, is an established treatment for Crohn's disease but not ulcerative colitis. Two randomized, double-blind, placebo-controlled studies--the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)--evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilogram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2. In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who received 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical response at week 8, as compared with 29 percent of those who received placebo (P<0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P< or =0.002 for all comparisons). In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical response at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons). Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (ClinicalTrials.gov numbers, NCT00036439 and NCT00096655.) Copyright 2005 Massachusetts Medical Society.

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Vedolizumab as induction and maintenance therapy for ulcerative colitis.

Brian Feagan, Paul Rutgeerts, Bruce Sands … (2013)

Gut-selective blockade of lymphocyte trafficking by vedolizumab may constitute effective treatment for ulcerative colitis. We conducted two integrated randomized, double-blind, placebo-controlled trials of vedolizumab in patients with active disease. In the trial of induction therapy, 374 patients (cohort 1) received vedolizumab (at a dose of 300 mg) or placebo intravenously at weeks 0 and 2, and 521 patients (cohort 2) received open-label vedolizumab at weeks 0 and 2, with disease evaluation at week 6. In the trial of maintenance therapy, patients in either cohort who had a response to vedolizumab at week 6 were randomly assigned to continue receiving vedolizumab every 8 or 4 weeks or to switch to placebo for up to 52 weeks. A response was defined as a reduction in the Mayo Clinic score (range, 0 to 12, with higher scores indicating more active disease) of at least 3 points and a decrease of at least 30% from baseline, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1. Response rates at week 6 were 47.1% and 25.5% among patients in the vedolizumab group and placebo group, respectively (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6 to 31.7; P 1), as compared with 15.9% of patients who switched to placebo (adjusted difference, 26.1 percentage points for vedolizumab every 8 weeks vs. placebo [95% CI, 14.9 to 37.2; P<0.001] and 29.1 percentage points for vedolizumab every 4 weeks vs. placebo [95% CI, 17.9 to 40.4; P<0.001]). The frequency of adverse events was similar in the vedolizumab and placebo groups. Vedolizumab was more effective than placebo as induction and maintenance therapy for ulcerative colitis. (Funded by Millennium Pharmaceuticals; GEMINI 1 ClinicalTrials.gov number, NCT00783718.).

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Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.

K Schroeder, W J Tremaine, D Ilstrup (1987)

We assessed oral 5-aminosalicylic acid (5-ASA) prepared with a pH-sensitive polymer coating in 87 patients with mildly to moderately active ulcerative colitis in a double-blind, placebo-controlled trial. Patients were randomly assigned to receive 5-ASA at a dosage of either 4.8 or 1.6 g per day or placebo for six weeks. The outcome was monitored by flexible proctosigmoidoscopic examinations and physicians' assessments at three-week intervals and by patients' recordings of daily symptoms. Results showed 24 percent complete and 50 percent partial responses in those receiving 4.8 g of 5-ASA per day as compared with 5 percent complete and 13 percent partial responses in those receiving placebo (P less than 0.0001, rank-sum test). At a dosage of 1.6 g per day, the response was twice as good as with placebo, but the difference did not reach statistical significance (P = 0.51). Age, sex, duration of disease, duration of active symptoms, or extent of disease did not affect the clinical outcome. We conclude that oral 5-ASA administered in a dosage of 4.8 g per day is effective therapy, at least in the short term, for mildly to moderately active ulcerative colitis.

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Author and article information

Contributors

Toshihiro Kita:

ORCID: http://orcid.org/0000-0003-1903-9012

toshihiro_kita@med.miyazaki-u.ac.jp

Journal

Journal ID (nlm-ta): J Gastroenterol

Journal ID (iso-abbrev): J Gastroenterol

Title: Journal of Gastroenterology

Publisher: Springer Singapore (Singapore )

ISSN (Print): 0944-1174

ISSN (Electronic): 1435-5922

Publication date (Electronic): 2 November 2020

Publication date PMC-release: 2 November 2020

Publication date (Print): 2021

Volume: 56

Issue: 2

Pages: 147-157

Affiliations

[1 ]GRID grid.410849.0, ISNI 0000 0001 0657 3887, Division of Circulatory and Body Fluid Regulation, Department of Internal Medicine, Faculty of Medicine, , University of Miyazaki, ; 5200 Kihara, Miyazaki, Miyazaki 889-1692 Japan

[2 ]GRID grid.256115.4, ISNI 0000 0004 1761 798X, Department of Gastroenterology, , Fujita Health University School of Medicine, ; Toyoake, Japan

[3 ]GRID grid.417362.5, IBD Center, , Yokkaichi Hazu Medical Center, ; Yokkaichi, Japan

[4 ]GRID grid.26091.3c, ISNI 0000 0004 1936 9959, Division of Gastroenterology and Hepatology, Department of Internal Medicine, , Keio University School of Medicine, ; Tokyo, Japan

[5 ]GRID grid.415268.c, ISNI 0000 0004 1772 2819, IBD Center, , Sapporo Kosei General Hospital, ; Sapporo, Japan

[6 ]GRID grid.411497.e, ISNI 0000 0001 0672 2176, Department of Gastroenterology and Medicine, Faculty of Medicine, , Fukuoka University, ; Fukuoka, Japan

[7 ]GRID grid.263171.0, ISNI 0000 0001 0691 0855, Department of Gastroenterology and Hepatology, , Sapporo Medical University School of Medicine, ; Sapporo, Japan

[8 ]GRID grid.177174.3, ISNI 0000 0001 2242 4849, Department of Medicine and Clinical Science, Graduate School of Medical Sciences, , Kyushu University, ; Fukuoka, Japan

[9 ]GRID grid.27476.30, ISNI 0000 0001 0943 978X, Department of Gastroenterology and Hepatology, , Nagoya University Graduate School of Medicine, ; Nagoya, Japan

[10 ]GRID grid.265050.4, ISNI 0000 0000 9290 9879, Department of Gastroenterology, Department of Internal Medicine, , Toho University Sakura Medical Center, ; Sakura, Japan

[11 ]GRID grid.258333.c, ISNI 0000 0001 1167 1801, Digestive and Lifestyle Diseases, , Kagoshima University Graduate School of Medical and Dental Sciences, ; Kagoshima, Japan

[12 ]GRID grid.415395.f, ISNI 0000 0004 1758 5965, Center for Advanced IBD Research and Treatment, , Kitasato University Kitasato Institute Hospital, ; Tokyo, Japan

[13 ]GRID grid.440090.9, ISNI 0000 0004 4667 0843, Department of Gastroenterology, , Idzuro Imamura Hospital, ; Kagoshima, Japan

[14 ]GRID grid.416855.b, Coloproctology Center Takano Hospital, ; Kumamoto, Japan

[15 ]GRID grid.410781.b, ISNI 0000 0001 0706 0776, Division of Gastroenterology, Department of Medicine, , Kurume University School of Medicine, ; Kurume, Japan

[16 ]GRID grid.410849.0, ISNI 0000 0001 0657 3887, Department of Gastroenterology and Hematology, Faculty of Medicine, , University of Miyazaki, ; Miyazaki, Japan

[17 ]GRID grid.413918.6, Department of Gastroenterology, , Fukuoka University Chikushi Hospital, ; Fukuoka, Japan

Author information

Toshihiro Kita http://orcid.org/0000-0003-1903-9012

Article

Publisher ID: 1741

DOI: 10.1007/s00535-020-01741-4

PMC ID: 7862507

PubMed ID: 33140199

SO-VID: d4d75eb5-a0a9-40ea-b21e-850b9b37c210

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 25 August 2020

Date accepted : 18 October 2020

Funding

Funded by: Japanese Agency for Medical Research and Development

Award ID: JP17ek0109089

Award Recipient : Kazuo Kitamura

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: adrenomedullin,ulcerative colitis,phase 2a clinical trial,japanese

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ScienceOpen disciplines: Gastroenterology & Hepatology

Keywords: adrenomedullin, ulcerative colitis, phase 2a clinical trial, japanese

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Adrenomedullin for steroid-resistant ulcerative colitis: a randomized, double-blind, placebo-controlled phase-2a clinical trial

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Abstract

Background

Methods

Results

Conclusions

Clinical trial registry

Electronic supplementary material

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Karger: Gastroenterology

Most cited references 29

Infliximab for induction and maintenance therapy for ulcerative colitis.

Vedolizumab as induction and maintenance therapy for ulcerative colitis.

Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study.

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Cited by 8

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