| 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 evaluate the effects of AMT-101 in combination with adalimumab on ulcerative colitis (UC) disease activity as measured by symptoms, endoscopy, histology, and biomarkers |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- To evaluate the safety and tolerability of AMT-101 over 8 weeks
- To assess the pharmacokinetic (PK) parameters of AMT-101 in combination with adalimumab
- To assess health-related quality of life (HRQOL)
- To assess the pharmacodynamic (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. Eligible for adalimumab therapy.
5. Naïve to therapy with approved or investigational biologics/tofacitinib including any anti-tumor necrosis factor (TNF) therapy, vedolizumab, or ustekinumab.
6. 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).
Note: subjects may be using 5-ASA and only 1 of the other medications listed (oral corticosteroids/6 MP/AZA/MTX).
7. If subjects are receiving bile-salt sequestrant, they must be on a stable dose for at least 3 months prior to randomization.
8. 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.
9. Unlikely to conceive.
10. 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.
11. Able to participate fully in all aspects of this clinical trial.
12. 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 hepatitisB 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. Any prior treatment with an approved or investigational biologic/tofacitinib, including anti-TNF therapy, vedolizumab, or ustekinumab.
9. Treatment with sirolimus, cyclosporine, mycophenolate, or tacrolimus within 8 weeks prior to randomization.
10. Treatment with IV corticosteroids, rectal corticosteroids, or rectal 5-ASA within 4 weeks prior to randomization.
11. Fecal microbiota transplantation within 1 month prior to screening.
12. 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.
13. A diagnosis of multiple sclerosis or optic neuritis, or history of a demyelinating disorder.
14. Known primary or secondary immunodeficiency.
15. 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.
16. Clinically meaningful laboratory abnormalities at screening that would affect subject safety, as determined and documented by the investigator.
17. Pregnant or lactating females.
18. Any surgical procedure requiring general anesthesia within 1 month prior to screening, or planned elective surgery during the study.
19. History of malignant neoplasms or carcinoma in situ within 5 years prior to screening.
20. 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.
21. Mental or legal incapacitation or a history of clinically significant psychiatric disorders at the time of the screening visit that would impact the ability to participate in the trial according to the investigator.
22. Unable to attend study visits or comply with procedures.
23. Concurrent participation in any other interventional study or received any investigational therapy within 1 month of randomization.
24. Previous exposure to AMT-101 or recombinant human interleukin-10 (rhIL-10).
25. A known hypersensitivity to AMT-101, adalimumab, or their respective excipients.
26. 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 UC-100 score from baseline
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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:
- Mean change in Robarts Histopathology Index (RHI) from baseline
- Mean change in total Mayo Clinic Score (MCS) and component scores (Mayo Endoscopic Subscore [MES], partial MCS, rectal bleeding and stool frequency) from baseline
- Mean change in fecal calprotectin from baseline
- Mean change in high-sensitivity C-reactive protein (hs CRP) from baseline
- Endoscopic remission rate (defined as a MES of 0 or 1)
- Endoscopic response rate (defined as a decrease from baseline in MES of at least 1 point)
- Mucosal healing rate (defined as MES of 0 or 1 and a Geboes Histologic Index score of ≤ 3.1)
- Histologic remission rate (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)
- Proportion of subjects who achieve a 50% reduction in RHI
- Clinical remission rate (defined as total MCS ≤ 2 with all subscores ≤ 1)
- Clinical response rate (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)
- Clinical remission rate (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)
- Changes in clinical chemistry and hematology from baseline
- Changes in vital signs and physical examinations from baseline
- Electrocardiogram (ECG) findings
Secondary Exploratory Endpoints:
- Concentrations of AMT-101, AMT-101 antidrug antibodies (ADAs), total interleukin-10 (IL-10), adalimumab, and adalimumab ADAs in serum
- Concentrations of AMT-101, AMT-101 ADAs, and total IL-10 in mucosal tissue biopsies
- Mean change in Inflammatory Bowel Disease Questionnaire (IBDQ) score from baseline
- Change in white blood cell count
- Change in fecal matrix metalloproteinase 9 (MMP-9)
- Change in fecal lactoferrin
- Change in interleukin-1 receptor antagonist (IL-1Ra)
- Change in serum and mucosal tissue protein levels
- Change in mucosal tissue gene expression
- Change in mucosal tissue cell populations
- Change in fecal microbiome
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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 | Yes |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Poland |
| Netherlands |
| Georgia |
| Ukraine |
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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 | 3 |
| E.8.9.1 | In the Member State concerned days | 26 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 29 |
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