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A Phase 2, Randomized, Double-Blinded, Placebo-Controlled, Parallel Group Study Evaluating the Efficacy and Safety of Amiselimod (MT-1303) in Subjects with Mild to Moderate Ulcerative Colitis (UC)

A Phase 2, Randomized, Double-Blinded, Placebo-Controlled, Parallel Group Study Evaluating the Efficacy and Safety of Amiselimod (MT-1303) in Subjects with Mild to Moderate Ulcerative Colitis (UC)

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A total of 322 subjects were enrolled in the study. One enrolled subject never received study treatment. For the Double-Blind Period, 321 subjects received study treatment: 107 in Group A (low dose amiselimod), 107 in Group B (high dose amiselimod), and 107 in Group C (placebo). For the OLE Period, 283 subjects received study treatment: 93 in Group A, 95 in Group B, and 95 in Group C. Overall, 237 subjects (73.8%) completed both the Double-Blind Period and the OLE Period. Subjects who Completed Study Treatment (Double-Blind): Group A: 94 (87.9%), Group B: 96 (89.7%), Group C: 95 (88.8%) Subjects who Completed Study (Open-Label Extension): Group A: 83 (77.6%), Group B: 74 (69.2%), Group C: 80 (74.8%)

For the Double-Blind Period, 321 subjects received study treatment: 107 in Group A (low dose amiselimod), 107 in Group B (high dose amiselimod), and 107 in Group C (placebo). Of these 321 subjects in the Intent-to-Treat (ITT) Population, 36 (11.2%) discontinued the study treatment and 36 (11.2%) discontinued the study during the Double-Blind Period (note: these 2 classifications include many of the same subjects. Two subjects (0.6%) completed the Double-Blind Period but did not enter the OLE Period. For the Open-Label Extension(OLE) Period, 283 subjects received study treatment: 93 in Group A (low dose amiselimod), 95 in Group B (high dose amiselimod), and 95 in Group C (placebo). During the OLE Period, 37 (11.5% of the ITT Population) discontinued study treatment and 46 (14.3% of the ITT Population) discontinued the study (note: these 2 classifications include many of the same subjects). Overall, 237 subjects (73.8%) completed both the Double-Blind Period and the OLE Period. Subjects who Completed Study Treatment (Double-Blind): Group A: 94 (87.9%), Group B: 96 (89.7%), Group C: 95 (88.8%) Subjects who Completed Study (Open-Label Extension): Group A: 83 (77.6%), Group B: 74 (69.2%), Group C: 80 (74.8%)

In the Double-Blind Period, 156 of the 321 subjects (48.6%) experienced a total of 327 TEAEs. The percentage of subjects with TEAEs was greatest in the amiselimod high dose group, followed by the amiselimod low dose group and the placebo group (57.0%, 47.7%, and 41.1%, respectively). The most frequently reported treatment-related TEAE was leukopenia, which occurred in 15.9% of subjects in the amiselimod high dose group and 7.5% of subjects in the amiselimod low dose group.Most subjects who experienced TEAEs (n=156) during the Double-Blind Period had events that were mild (n=80) or moderate (n=70) in severity (150 of 156 [96.2%]). A similar percentage was seen for all 3 treatment groups. Severe TEAEs were reported in 3 or fewer subjects in each treatment group. Overall, colitis ulcerative was the only severe TEAE reported in more than 1 subject (1 subject in amiselimod low dose group and 1 subject in placebo group). Six subjects (1.9%) had a total of 6 serious TEAEs in the Double-Blind Period. The percentage of subjects who reported serious TEAEs was greater in the amiselimod groups (3 subjects [2.8%] in high dose and 2 subjects [1.9%] in low dose) compared to the placebo group (1 subject [0.9%]). The most common serious TEAE was colitis ulcerative, which occurred in 4 subjects (1.2%) overall and in all 3 treatment groups. In the OLE Period, 203 of the 283 subjects (71.7%) experienced a total of 538 TEAEs. The most frequently reported TEAEs were lymphopenia (28.3% of subjects), leukopenia (15.5% of subjects), and colitis ulcerative (10.2% of subjects).Most subjects who experienced TEAEs (n=203) during the OLE Period had events that were mild (n=90) or moderate (n=102) in severity (192 of 203 [94.6%]). Severe TEAEs occurred in 11 subjects (3.9%). Overall, colitis ulcerative was the only severe TEAE reported in more than 1 subject (3 subjects total). Sixteen subjects (5.7%) had a total of 18 serious TEAEs in the OLE Period. The most common serious TEAE was colitis ulcerative, which occurred in 6 subjects (2.1%).

Primary Endpoint: In the full ITT Population, amiselimod (at both the low dose and the high dose) was superior to placebo based on the change from baseline in the mMS at Day 85.The decrease from baseline in mMS was similar for the amiselimod low dose group and the amiselimod high dose group (mean [SD]: -2.3 [2.18] and -2.3 [2.21], respectively), and both amiselimod groups showed a numerically larger decrease from baseline than that in the placebo group (mean [SD]: -1.6 [2.17]). The LS mean difference between the amiselimod low dose group and the placebo group was statistically significant (-0.74 [p = 0.010]), and the LS mean difference between the amiselimod high dose group and the placebo group was statistically significant (-0.76 [p = 0.008]). Secondary Endpoints: Endoscopic improvement at Day 85: Low dose: 41.1%, High dose: 43.0%, Placebo: 23.4%. The difference in percentages between the amiselimod low dose group and the placebo group was statistically significant (17.4% [p = 0.007]), and the difference in percentages between the amiselimod high dose group and placebo group was statistically significant (19.4% [p = 0.003]). The decrease from baseline in 2-component mMS at Day 85 was similar in the amiselimod low dose group and the amiselimod high dose group (mean [SD]: -1.6 [1.58] and -1.6 [1.61], respectively), and both amiselimod groups showed a larger decrease than the placebo group (mean [SD]: -1.0 [1.51]). The LS mean difference between the amiselimod low dose group and the placebo group was statistically significant (-0.61 [p = 0.003]), and the LS mean difference between the amiselimod high dose group and placebo group was statistically significant (-0.61 [p = 0.002]). Clinical remission at Day 85 (FDA 2022 definition): Low dose: 32.7%, High dose: 30.8%, Placebo: 17.8%. The difference in percentages between the amiselimod low dose group and the placebo group was statistically significant (14.6% [p = 0.015]), and the difference in percentages between the amiselimod high dose group and the placebo group was statistically significant (12.9% [p = 0.029]).

The primary endpoint was met showing amiselimod (low and high dose) was superior to placebo for change from baseline in mMS at Day 85. Secondary endpoints (endoscopic improvement, 2-component Mayo Score, and clinical remission) supported this conclusion, with statistically significant differences for both amiselimod doses versus placebo. Amiselimod was well-tolerated, with no unexpected safety findings. The observed safety profile was consistent with the class safety profile for S1P receptor modulators.

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210352

Jimin Lee

Salix Pharmaceuticals, Inc

400 Somerset Corporate Blvd., Bridgewater, NJ, USA

Jimin.lee@baushhealth.com

Jimin Lee

Salix Pharmaceuticals, Inc

400 Somerset Corporate Blvd., Bridgewater, NJ, USA

908-541-2138

Jimin.lee@baushhealth.com

Complete

Sept. 20, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Male or female subjects aged between 18 to 75 years (inclusive) at the time of the subject's signing of the informed consent.
2. Normal vital signs.
- afebrile,
- heart rate 55-100 bpm,
- systolic blood pressure >90 and <150 mmHg,
- diastolic blood pressure >50 and <90 mmHg,
- respiration rate >10 and <20/min. 3. Diagnosis of active mild to moderate UC (modified Mayo Score of 3 to 8) confirmed at least 12 weeks prior to randomization by clinical and endoscopic evidence (corroborated by a histopathology report).
- Mild UC is defined as a modified Mayo Score of 3 or 4.
- Moderate UC is defined as a modified Mayo Score of 5 to 8.
4. An endoscopic subscore from screening colonoscopy of >=2 as determined by a central reviewer.
5. Evidence of active UC extending >=15 cm from the anal verge confirmed by a screening colonoscopy.
6. If subjects are receiving oral or rectal 5-aminosalicylates (5-ASAs) or oral corticosteroids (<=20 mg prednisolone equivalent) for treatment of their UC, they must be on a stable dose for at least 28 days prior to randomization.
7. All women of childbearing potential (WOCBP) must have a negative serum pregnancy test at the Screening Visit and a urine pregnancy test at each subsequent study visit and agree to use an acceptable method of contraception throughout their participation in the study and for 12 weeks after the last dose of IMP. See Section 7.6 for details on methods of contraception.
8. Willingness and ability to complete training in the use of the subject diary and to complete the subject diary in a timely manner throughout the study.

Exclusion Criteria Related to Ulcerative Colitis
1. Diagnosis of Crohn's disease, indeterminate colitis, colitis (pseudomembranous, microscopic, or ischemic) or coeliac disease.
2. Current or recent (within 12 weeks prior to randomization) evidence of fulminant colitis, abdominal abscess, toxic megacolon, bowel obstruction, or bowel perforation.
3. Diagnosis of proctitis, defined as a rectal inflammation within 15 cm from the anal verge.
4. History or evidence of any colonic resection or subtotal colectomy within 1 year prior to randomization.
5. History or evidence of ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine.
6. History or evidence of unresected adenomatous colonic polyps or colonic mucosal dysplasia.
7. Current need for, or anticipated need for surgical intervention for UC during the study.

Both

Ulcerative Colitis

Double-blinded Treatment Period : Oral administration of 2 capsules of 0.2 mg or 0.4 mg amiselimod or placebo once a day for 2 weeks, and oral administration of one cupsule once a day for 10 weeks. Open Label Extension Period: Oral administration of 0.4 mg amiselimod once a day for up to 36 weeks.

The modified Mayo Score will be used for the primary efficacy evaluation.

Aug. 16, 2021

USA/Australia/Taiwan/S. Korea/Belarus/Russia/Ukraine/Moldova/Georgia/Germany/Hungary/Czech Republic/Slovakia,/Serbia/Italy/ Estonia/Bulgaria/Poland