E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Ulcerative colitis is a form of inflammatory bowel disease (IBD) that causes inflammation and ulcers in the colon resulting in abdominal pain and bloody diarrhea
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045365 |
E.1.2 | Term | Ulcerative colitis |
E.1.2 | System Organ Class | 100000004856 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of repeated oral doses of AMT-101 versus placebo to reduce Mayo Endoscopic Subscore (MES) at Week 12 in adult subjects with moderate to severe UC |
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E.2.2 | Secondary objectives of the trial |
Secondary Objectives: - To evaluate the effects of AMT-101 on disease activity as measured by symptoms, endoscopy, histology, and biomarkers over 12 weeks - To evaluate safety and tolerability of oral AMT-101 over 12 weeks - To assess the pharmacokinetic (PK) parameters of AMT-101 - To assess health-related quality of life (HRQOL)
Exploratory Objectives: - To assess the pharmacodynamic (PD) effect of AMT-101 on inflammation - To assess the PK parameters of AMT-101 in mucosal tissue - To assess the PD effect of AMT-101 on biomarkers - To assess target engagement and mechanism of action
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
The study will enroll male and female adult subjects with moderate to severe UC.
Inclusion criteria (subjects must meet the following criteria to be randomized into the study): 1. Male and female subjects aged 18 to 75 years, inclusive. 2. Diagnosis of UC for at least 3 months prior to screening. 3. Moderate to severe UC, as defined by a total MCS of 6 to 12 inclusive at baseline, with a MES ≥ 2 (confirmed by central reader). 4. If subjects have previously received any biologic (i.e., tumor necrosis factor [TNF] antagonists, vedolizumab, ustekinumab) or tofacitinib therapy, they must meet the following: a. Biologics: a washout period of at least 12 weeks or 5 half-lives prior to randomization, or a washout period of at least 4 weeks prior to randomization if biologic drug levels are undetectable. b. Tofacitinib: a washout period of at least 4 weeks prior to randomization. c. Cannot have failed both biologic and tofacitinib for UC. Note: No more than 51 subjects (50% of the total study population) with prior exposure to these therapies will be randomized into the study including no more than 20 subjects (20% of the total study population) with exposure to more than 1 biologic/tofacitinib therapy. 5. If subjects are receiving the following treatments, they must be on a stable dose for at least 4 weeks prior to randomization: a. 5-Aminosalicylates (5-ASAs) (not exceeding 4.8 g per day). b. Oral corticosteroids (not exceeding prednisone 20 mg, budesonide 9 mg, or equivalent). c. 6-Mercaptopurine (6-MP) (any stable dose). d. Azathioprine (AZA) (any stable dose). e. Methotrexate (MTX) (any stable dose). 6. If subjects are receiving bile-salt sequestrant, they must be on a stable dose for at least 3 months prior to randomization. 7. If subjects are receiving any nonprohibited medications, they must agree to maintain stable doses of concomitant medications for UC until the end of the safety follow-up period. 8. Unlikely to conceive. 9. Women of childbearing potential (WOCBP) must have a negative pregnancy test at screening and at the randomization visit prior to the first dose of study drug. 10. Able to participate fully in all aspects of this clinical trial. 11. Written informed consent must be obtained and documented.
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E.4 | Principal exclusion criteria |
Exclusion criteria (subjects who exhibit any of the following criteria are to be excluded from the study): 1. A diagnosis of Crohn’s disease (CD), indeterminate colitis, or presence or history of fistula with CD. 2. Disease activity limited to distal 15 cm (proctitis). 3. Current evidence of toxic megacolon, abdominal abscess, symptomatic colonic stricture, or stoma. 4. History or current evidence of colonic dysplasia or adenomatous colonic polyps. 5. Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile; known active cytomegalovirus infection; known infection with hepatitis B or C virus; known infection with human immunodeficiency virus; infection requiring hospitalization or intravenous (IV) antimicrobial therapy, or opportunistic infection within 6 months prior to screening; any infection requiring antimicrobial therapy within 2 weeks prior to screening; history of more than 1 episode of herpes zoster or any episode of disseminated zoster. 6. A positive diagnostic tuberculosis (TB) test at screening (defined as a positive QuantiFERON test). In cases where the QuantiFERON test is indeterminate, the participant may have the test repeated once and if their second test is negative they will be eligible. In the event a second test is also indeterminate, or QuantiFERON is unavailable, the investigator has the option to perform a purified protein derivative (PPD) skin test. If the PPD reaction is < 5 mm, then the subject is eligible. If the reaction is ≥ 5 mm, or PPD testing is not done, the subject is not eligible. An exception is made for subjects with a history of latent TB who are currently receiving treatment for latent TB, will initiate treatment for latent TB before the first dose of study treatment, or have documentation of completing appropriate treatment for latent TB within 3 years prior to the first dose of study treatment). 7. Live virus vaccination within 1 month prior to screening. 8. Treatment with sirolimus, cyclosporine, mycophenolate, or tacrolimus within 8 weeks prior to randomization. 9. Treatment with IV corticosteroids, rectal corticosteroids, or rectal 5-ASA within 4 weeks prior to randomization. 10. Fecal microbiota transplantation within 1 month prior to screening. 11. A concurrent clinically significant, serious, unstable, or uncontrolled underlying cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, might confound the study results, pose additional risk to the subject, or interfere with the subject’s ability to participate fully in the study. 12. Known primary or secondary immunodeficiency. 13. History of myocardial infarction, unstable angina, transient ischemic attack, decompensated heart failure requiring hospitalization, congestive heart failure (New York Heart Association Class 3 or 4), uncontrolled arrhythmias, cardiac revascularization, stroke, uncontrolled hypertension, or uncontrolled diabetes within 6 months of screening. 14. Clinically meaningful laboratory abnormalities at screening that would affect subject safety, as determined and documented by the investigator. 15. Pregnant or lactating females. 16. Any surgical procedure requiring general anesthesia within 1 month prior to screening, or planned elective surgery during the study. 17. History of malignant neoplasms or carcinoma in situ within 5 years prior to screening. 18. Current or recent history of alcohol dependence or illicit drug use that, in the opinion of the investigator, may interfere with the subject’s ability to comply with the study procedures. 19. Mental or legal incapacitation or a history of clinically significant psychiatric disorders at the time of screening visit that would impact the ability to participate in the trial according to the investigator. 20. Unable to attend study visits or comply with procedures. 21. Concurrent participation in any other interventional study or received any investigational therapy within 1 month of randomization. 22. Previous exposure to AMT-101 or recombinant human interleukin-10 (rhIL-10). 23. A known hypersensitivity to AMT-101 or its excipients. 24. Current treatment with antimotility medications or antidiarrheals (except for bile-salt sequestrants).
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E.5 End points |
E.5.1 | Primary end point(s) |
Mean change in MES from baseline to Week 12
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints: - Endoscopic remission rate at Week 12 (defined as a MES of 0 or 1) - Endoscopic response rate at Week 12 (defined as a decrease from baseline in MES of at least 1 point) - Mucosal healing rate at Week 12 (defined as MES of 0 or 1 and a Geboes Histologic Index score of ≤ 3.1) - Histologic remission rate at Week 12 (defined as Geboes Histologic Index score of ≤ 2B.0; or Robarts Histopathology Index [RHI] ≤ 3 with subscores of 0 for lamina propria neutrophils and 0 for neutrophils in epithelium) - Clinical remission rate at Week 12 (defined as total MCS ≤ 2 with all subscores ≤ 1) - Clinical response rate at Week 12 (defined as decrease from baseline in MCS of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1) - Mean change in partial MCS from baseline to Weeks 2, 6, and 12 - Mean change in Mayo rectal bleeding subscore from baseline to Weeks 2, 6, and 12 - Mean change in Mayo stool frequency subscore from baseline to Weeks 2, 6, and 12 - Proportion of subjects with a Geboes Histologic Index score ≤ 3.1 at Week 12 - Mean change in RHI scores from baseline to Week 12 - Mean change in fecal calprotectin from baseline to Weeks 2, 6, and 12 - Mean change in high-sensitivity C-reactive protein (hs CRP) from baseline to Weeks 2, 6, and 12 - Clinical remission rate at Week 12 (alternative definition of Mayo stool frequency subscore of 0 or 1 and Mayo rectal bleeding subscore of 0 and MES of 0 or 1)
Secondary Safety Endpoints: - Frequency and severity of adverse events (AEs) compared to placebo - Changes in clinical chemistry and hematology from baseline - Results of vital signs and physical examination - Electrocardiogram (ECG) findings
Secondary PK Endpoints: - Concentrations of AMT-101, AMT-101 antidrug antibodies (ADAs), and total IL-10 in serum
Secondary HRQOL Endpoints: - Mean change in Symptoms and Impacts Questionnaire for UC (SIQ-UC) from baseline to Week 12 - Mean change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline to Week 12, comparing AMT-101 to placebo
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 37 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
India |
United States |
France |
Poland |
Bulgaria |
Netherlands |
Romania |
Switzerland |
Germany |
Italy |
Belarus |
Belgium |
Georgia |
Hungary |
Kazakhstan |
Moldova, Republic of |
Russian Federation |
Serbia |
Ukraine |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |