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

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.

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A Multicentre, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy, Safety, and Tolerability of the S1P Receptor Agonist KRP203 in Patients with Moderately Active Refractory Ulcerative Colitis

Inflammatory Intestinal Diseases ◽

10.1159/000509393 ◽

2020 ◽

Vol 5 (4) ◽

pp. 180-190

Author(s):

Heinfried H. Radeke ◽

Jürgen Stein ◽

Gert Van Assche ◽

Gerhard Rogler ◽

Peter L. Lakatos ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Remission ◽

Receptor Subtype ◽

Double Blind ◽

Double Blind Placebo ◽

Peripheral Lymphocytes ◽

Mayo Score ◽

Parallel Group ◽

The Difference ◽

Improved Design

Background and Aims: KRP203 is a potent oral agonist of the sphingosine-1-phosphate receptor subtype 1 that induces the sequestration of peripheral lymphocytes, thereby potentially reducing the number of activated lymphocytes circulating to the gastrointestinal tract. Methods: We conducted a multicentre, double-blind, placebo-controlled, parallel-group, proof-of-concept study to evaluate the efficacy, safety, and tolerability of KRP203 in patients with moderately active 5-aminosalicylate-refractory ulcerative colitis (UC). Patients were randomly assigned to receive 1.2 mg KRP203 or placebo daily for 8 weeks. Primary efficacy variable was clinical remission, defined as partial Mayo Score 0–1 and modified Baron Score 0–1 with rectal bleeding subscore 0. Results: KRP203 was safe and well tolerated overall. The most common adverse events (AEs) were gastrointestinal disorders and headache. Importantly, no KRP203-related cardiac AEs were reported. Total peripheral lymphocytes and selectively affected lymphocyte subtypes decreased, causing marked decreases in naive and central memory CD4+ and CD8+ T cells, and also in B cells. Clinical remission occurred in 2/14 (14%) patients under KRP203, compared with 0/8 (0%) under placebo. Conclusions: Overall, KRP203 was safe and well tolerated by patients with UC. Importantly, no cardiac AEs were reported. Although KRP203 did not meet the minimum clinically relevant threshold for efficacy, the results may suggest that KRP203 treatment is superior to placebo. However, in this small study population, the difference was insignificant. Based on these data, studies with an improved design and a larger population should be considered.

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Efficacy and safety of a standardized extract from Achillea wilhelmsii C. Koch in patients with ulcerative colitis: A randomized double blind placebo-controlled clinical trial

Complementary Therapies in Medicine ◽

10.1016/j.ctim.2019.05.001 ◽

2019 ◽

Vol 45 ◽

pp. 262-268 ◽

Cited By ~ 2

Author(s):

Mahtab Amiri ◽

Jafar Navabi ◽

Yalda Shokoohinia ◽

Fatemeh Heydarpour ◽

Gholamreza Bahrami ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Trial ◽

Controlled Clinical Trial ◽

Efficacy And Safety ◽

Double Blind ◽

Double Blind Placebo ◽

Achillea Wilhelmsii

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Novel STAT3 Selective Inhibitor Natura-α Shows Great Promises in Treating Moderate-to-severe Ulcerative Colitis in a Randomized, Double-blind, Placebo-controlled Phase II Clinical Trial

The American Journal of Gastroenterology ◽

10.14309/00000434-201210001-01582 ◽

2012 ◽

Vol 107 ◽

pp. S638

Author(s):

Longgui Wang ◽

Simon Mencher ◽

Sunil Khurana ◽

Barry Kaufman ◽

Robert Hardi ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Trial ◽

Phase Ii ◽

Selective Inhibitor ◽

Phase Ii Clinical Trial ◽

Double Blind ◽

Double Blind Placebo ◽

Severe Ulcerative Colitis

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The Efficacy and Safety of Shen Guo Lao Nian Granule for Common Cold of Qi-Deficiency Syndrome: Study Protocol for a Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase II Clinical Trial

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/1806461 ◽

2017 ◽

Vol 2017 ◽

pp. 1-11

Author(s):

Xuemei Liu ◽

Juanjuan Fu ◽

Tao Fan ◽

Wei Liu ◽

Hongli Jiang ◽

...

Keyword(s):

Clinical Trial ◽

Phase Ii ◽

Study Protocol ◽

Common Cold ◽

Dose Group ◽

Deficiency Syndrome ◽

Phase Ii Clinical Trial ◽

High Dose ◽

Double Blind ◽

Double Blind Placebo

Background. Common cold is one of the most frequently occurring illnesses in primary healthcare services and represents considerable disease burden. Common cold of Qi-deficiency syndrome (CCQDS) is an important but less addressed traditional Chinese medicine (TCM) pattern. We designed a protocol to explore the efficacy, safety, and optimal dose of Shen Guo Lao Nian Granule (SGLNG) for treating CCQDS. Methods/Design. This is a multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. A total of 240 eligible patients will be recruited from five centers. Patients are randomly assigned to high-dose group, middle-dose group, low-dose group, or control group in a 1 : 1 : 1 : 1 ratio. All drugs are required to be taken 3 times daily for 5 days with a 5-day follow-up period. Primary outcomes are duration of all symptoms, total score reduction on Jackson’s scale, and TCM symptoms scale. Secondary outcomes include every single TCM symptom duration and score reduction, TCM main symptoms disappearance rate, curative effects, and comparison between Jackson’s scale and TCM symptom scale. Ethics and Trial Registration. This study protocol was approved by the Ethics Committee of Clinical Trials and Biomedicine of West China Hospital of Sichuan University (number IRB-2014-12) and registered with the Chinese Clinical Trial Registry (ChiCTR-IPR-15006349).

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Therapeutic effect of high-dose green tea extract on weight reduction: A randomized, double-blind, placebo-controlled clinical trial

Clinical Nutrition ◽

10.1016/j.clnu.2015.05.003 ◽

2016 ◽

Vol 35 (3) ◽

pp. 592-599 ◽

Cited By ~ 105

Author(s):

I-Ju Chen ◽

Chia-Yu Liu ◽

Jung-Peng Chiu ◽

Chung-Hua Hsu

Keyword(s):

Clinical Trial ◽

Therapeutic Effect ◽

Green Tea ◽

Weight Reduction ◽

Green Tea Extract ◽

Controlled Clinical Trial ◽

High Dose ◽

Double Blind ◽

Double Blind Placebo ◽

Tea Extract

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Randomised clinical trial: high-dose acid suppression for chronic cough - a double-blind, placebo-controlled study

Alimentary Pharmacology & Therapeutics ◽

10.1111/j.1365-2036.2010.04511.x ◽

2010 ◽

Vol 33 (2) ◽

pp. 225-234 ◽

Cited By ~ 86

Author(s):

N. J. Shaheen ◽

S. D. Crockett ◽

S. D. Bright ◽

R. D. Madanick ◽

R. Buckmire ◽

...

Keyword(s):

Clinical Trial ◽

Chronic Cough ◽

Randomised Clinical Trial ◽

Acid Suppression ◽

Controlled Study ◽

High Dose ◽

Double Blind ◽

Double Blind Placebo

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OP24 Efficacy and safety of upadacitinib induction therapy in patients with Moderately to Severely Active Ulcerative Colitis: Results from the phase 3 U-ACHIEVE study

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab075.023 ◽

2021 ◽

Vol 15 (Supplement_1) ◽

pp. S022-S024

Author(s):

S Danese ◽

S Vermeire ◽

W Zhou ◽

A Pangan ◽

J Siffledeen ◽

...

Keyword(s):

Ulcerative Colitis ◽

Clinical Response ◽

Induction Therapy ◽

Clinical Remission ◽

Janus Kinase ◽

Phase 3 ◽

Mayo Score ◽

Significant Difference ◽

Endoscopic Remission ◽

Secondary Endpoints

Abstract Background An unmet therapeutic need remains in patients with ulcerative colitis (UC). U-ACHIEVE is one of two phase 3 induction trials evaluating the safety and efficacy of the selective Janus kinase–1 inhibitor upadacitinib (UPA) 45 mg once daily (QD) in adults with UC. Methods U-ACHIEVE is a multicentre, double-blind, placebo (PBO)–controlled trial (NCT02819635) that randomized patients with moderately to severely active UC 2:1 to UPA 45 mg QD or PBO for 8 weeks. Patients were stratified by response to biologic therapy (inadequate vs non–inadequate responder), baseline corticosteroid use (yes or no), and baseline adapted Mayo score (≤7 or >7). The primary endpoint was proportion of patients achieving clinical remission (per adapted Mayo Score) at week 8.Ranked secondary endpoints included endoscopic improvement, endoscopic remission, and clinical response per adapted Mayo Score at week 8; clinical response per partial adapted Mayo Score at week 2; and histologic-endoscopic mucosal improvement at week 8. Non-responder imputation incorporating multiple imputations for missing data due to COVID-19 are reported. Safety was assessed through week 8. Results 474 patients were randomized (UPA, n=319; PBO, n=155). Baseline characteristics were well balanced between groups (Table 1). A significantly higher proportion of patients receiving UPA (26.1%) vs PBO (4.8%) achieved clinical remission at week 8 (adjusted treatment difference [95% CI], 21.6% [15.8, 27.4]; P<0.001; Figure 1). For all ranked secondary endpoints, UPA was superior to PBO (P<0.001; Figure 1). A significant difference in clinical response favouring UPA vs PBO was seen as early as week 2 (60.1% vs 27.3%) and was sustained over 8 weeks (79.0% vs 41.6%; Figure 2). There were more serious adverse events (AEs), severe AEs, and AEs leading to study drug discontinuation with PBO (Table 2). The most common AEs were acne, creatine phosphokinase elevation, and nasopharyngitis with UPA and worsening of UC and anaemia with PBO. Incidence of serious infection was similar between UPA and PBO. Neutropenia and lymphopenia were reported more frequently with UPA vs PBO (Table 2).No adjudicated gastrointestinal perforation, major cardiovascular AEs, or thrombotic events and no active tuberculosis, malignancy, or deaths were reported. Conclusion In patients with moderately to severely active UC, UPA 45 mg QD induction therapy was superior to PBO in inducing clinical remission/response, and endoscopic remission/response over 8 weeks; responses were significant and rapid. UPA 45 mg QD was well tolerated; safety was comparable with the known safety profile of UPA, and no new safety signals were identified.

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