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 |
Inflammation of the ileal pouch - an artificial rectum surgically created out of ileal gut tissue in patients who have undergone a colectomy.
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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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10036463 |
E.1.2 | Term | Pouchitis |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
Phase 2 Study Objective: - To assess the safety, tolerability, systemic exposure, and efficacy of AMT-101 in subjects with chronic antibiotic-resistant pouchitis
Phase 3 Study Co-primary Objectives: - To determine the effect of AMT-101 on stool frequency in subjects with chronic antibiotic-resistant pouchitis - To determine the effect of AMT-101 on histologic disease activity in subjects with chronic antibiotic-resistant pouchitis
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E.2.2 | Secondary objectives of the trial |
Phase 2 Study Objective: - To select an AMT-101 dose for Phase 3
Phase 3 Study Objectives: - To assess the efficacy of AMT-101 on histologic, endoscopic, and other clinical signs and symptoms in subjects with chronic antibiotic-resistant pouchitis - To assess the safety and tolerability of AMT-101 in chronic antibiotic-resistant pouchitis - To assess the efficacy of AMT-101 to improve health-related quality of life (HRQOL) - To determine the systemic exposure of subjects following dosing
Exploratory Objectives (both Phases): - To assess the effect of AMT-101 to reduce time to rescue therapy - To assess the pharmacodynamic (PD) effect of AMT-101 on endoscopic and histologic inflammation - To determine the mucosal tissue exposure of subjects following dosing - To assess the PD effect of AMT-101 on change in biomarkers - To assess target engagement and mechanism of action - To assess the effect of AMT-101 on work productivity
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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 chronic antibiotic-resistant pouchitis. Inclusion criteria (subjects must meet the following criteria to be randomized into the study): 1. Male and female subjects aged 18 to 75 yrs, inclusive. 2. IPAA for UC completed at least 1 yr prior to screening. 3. Active signs and symptoms of pouchitis, as follows: a. Modified Pouchitis Disease Activity Index (mPDAI) score ≥ 5, and, b. Increased stool frequency, defined as 3 more stools per day above “normal” (after IPAA) and an absolute total of ≥ 6 stools per day. “Increased stool frequency” is calculated as the difference between “Normal” and “Screening stool frequency. “Normal” is the stool frequency achieved post-IPAA when the subject’s bowel function was most settled. This typically occurs approximately 1 year after IPAA and should be supported by documentation in the subject’s medical records. If stool frequency never normalized after IPAA, consult with the Medical Monitor to determine if pre-IPAA stool frequency is appropriate. To be eligible for the study, subjects must experience 6 or more stools per day, and this value must be 3 or more stools per day greater than the “Normal” value, as defined above. 4. Chronic or recurrent pouchitis, defined by: a. ≥ 2 episodes within 1 year prior to or including the screening period treated with antibiotic or other prescription therapy, or, b. Maintenance antibiotic therapy taken continuously for ≥4 weeks immediately prior to the screening endoscopy. 5. Antibiotic-resistant pouchitis, defined as disease remaining active despite at least 2 weeks of antibiotic therapy. 6. Histologic inflammation in the pouch, defined by a Geboes score of 3.1 or greater. 7. Unlikley to conceive. 8. 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. 9. Able to participate fully in all aspects of this clinical trial. 10. Written informed consent must be obtained and fully documented.
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E.4 | Principal exclusion criteria |
Exclusion criteria (subjects who meet any of the following criteria are not eligible for participation in the study): 1. Known Crohn’s disease (CD) or suspected CD of the pouch, defined as complex perianal/pouch fistula and/or extensive length of pre-pouch ileitis with deep ulceration. 2. Diagnosed or suspected irritable pouch syndrome (IPS). 3. Isolated or predominant cuffitis. 4. Mechanical complications of the pouch such as stricture or fistula(e) that preclude evaluation of the pouch and terminal ileum. 5. Fecal incontinence due to anal sphincter dysfunction. 6. Pelvic sepsis within 12 months prior to screening. 7. Planned surgery for UC, or any other elective surgery within the time frame of the study. 8. Diverting stoma. 9. Current bacterial or parasitic pathogenic enteric infection, including Clostridium difficile; known infection with hepatitis B or C virus; known infection with human immunodeficiency virus; infection requiring hospitalization or intravenous 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. 10. A positive diagnostic tuberculosis (TB) test at screening (defined as a positive QuantiFERON test). 11. Prior biologic use restrictions and exclusions: a. No more than 60% of enrolled subjects in Phase 2 and no more than 25% of enrolled subjects in Phase 3 may have prior failure of any biologics for pouchitis. b. Subjects who have used prior biologic therapies must have discontinued within 12 weeks or 5 half-lives of screening (or within 4 weeks if drug levels are undetectable). 12. Use of any of the following prohibited therapies, except under the stated conditions (if applicable): a. Opioids within 4 weeks prior to screening. b. Chronic use (>4 weeks of continuous use prior to screening) of nonsteroidal anti-inflammatory drugs, except for chronic use of low-dose 81 mg aspirin. c. Oral 5-aminosalicylate (5-ASA), unless the dose is ≤ 4.8 g/day and has been stable for at least 4 weeks prior to screening. d. Oral budesonide within 6 weeks of screening. e. Other oral corticosteroids at daily doses > 20 mg prednisone or equivalent, or who started oral corticosteroids within 6 weeks prior to screening; stable doses ≤ 20 mg prednisone or equivalent for at least 4 weeks prior to screening are permitted. f. Any rectal compounds. g. Immunosuppresant therapy (azathioprine, 6-mercaptopurine, methotrexate, cyclosporin) within 8 weeks prior to screening. h. Fecal transplant within 12 weeks prior to screening. i. Live virus vaccination within 1 month prior to screening. j. Any investigational therapy within 4 weeks prior to screening. 13. Diagnosed with any immune deficiency. 14. History of malignancy, except for basal cell carcinoma, nonmetastatic squamous cell carcinoma of the skin, or prior malignancy with curative therapy completed at least 5 years prior to screening and no recurrence. 15. Clinically meaningful laboratory abnormalities at screening that would affect subject safety, as judged by the investigator from local testing. 16. A concurrent, clinically significant, serious, unstable, or uncontrolled underlying cardiovascular, pulmonary, hepatic, renal, gastrointestinal, genitoruinary, hematological, coagulation, immunological, endocrine/metabolic, or other medical disorder that, in the opinion of the investigator, might confound study results, pose additional risk to the subject, or interfere with the subject’s ability to participate fully in the study. 17. 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. 18. Pregnant or lactating females. 19. Any surgical procedure requiring general anesthesia within 1 month prior to screening, or planned elective surgery during the study. 20. 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. 21. Concurrent participation in any other interventional study or received any investigational therapy within 1 month prior to screening. 22. Previous exposure to AMT-101. 23. A known hypersensitivity to AMT-101 or its excipients.
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-primary Efficacy Endpoints: - Proportion of subjects with a stool frequency response at Week 12; defined as a reduction of ≥ 3 stools AND ≥ 30% reduction in number of stools from baseline, OR back to postoperative baseline number of stools - Proportion of subjects with histologic healing at Week 12; defined as neutrophil infiltration in < 5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue (Geboes score < 3.1)
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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) |
Ranked efficacy endpoints: 1. Proportion of subjects with histologic response at Week 12; defined as a reduction in Pouchitis Disease Activity Index (PDAI) histology subscore ≥ 2 points from baseline or a PDAI histology subscore of 0 2. Proportion of subjects with minimal histologic activity at Week 12; defined as PDAI neutrophil score ≤ 1 and ulcer score of 0 3. Mean change in PDAI histologic subscore at Week 12 4. Proportion of subjects with 50% reduction in Simple Endoscopic Score for Crohn’s Disease (SES-CD) score at Week 12 (area within 1 cm of the pouch suture line will not be included in the endoscopic evaluation) 5. Mean change in PDAI endoscopic subscore at Week 12 6. Proportion of subjects achieving mPDAI < 5 and a reduction of overall score by ≥ 2 points from baseline at Week 12 7. Proportion of subjects achieving PDAI < 7 and a reduction of overall score by ≥ 3 points from baseline at Week 12 8. Proportion of subjects achieving a partial response at Week 12; defined as reduction of mPDAI score by ≥ 2 points from baseline 9. Mean change in stool frequency at Weeks 2, 6, 8, 10, 12, and 4WPT 10. Proportion of subjects with Mayo stool frequency score of 0 or 1 at Weeks 2, 6, 8, 10, 12, and 4WPT 11. Mean change in urgency score at Week 12 and 4WPT 12. Mean change in incontinence score (St. Mark’s) at Week 12 and 4WPT 13. Mean change in rectal bleeding score at Weeks 2, 6, 8, 10, 12, and 4WPT 14. Mean change in total PDAI score at Week 12
Safety, HRQOL, and pharmacokinetic (PK) endpoints: • Proportion of subjects with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and discontinuation due to TEAEs • Assessment of laboratory parameters • Assessment of vital signs • Mean change in Inflammatory Bowel Disease Questionnaire (IBDQ), 5-dimension EuroQoL questionnaire (EQ-5D), and 36-item Short-Form questionnaire (SF-36) at Week 12 and 4WPT • Concentration of AMT-101, AMT-101 antidrug antibodies (ADAs), and total interleukin-10 (IL-10) in serum at Week 12
Exploratory efficacy endpoints: • Time to relapse of pouchitis symptoms • Time to first use of rescue therapy • Increased use of antidiarrheals • Proportion of subjects with endoscopic remission; defined as absence of friability and ulceration, represented by a Mayo Endoscopic Subscore (MES) < 1 (area within 1 cm of the pouch suture line will not be included in the endoscopic evaluation) • Proportion of subjects with endoscopic remission; defined as a SES-CD score of ≤ 2 (area within 1 cm of the pouch suture line will not be included in the endoscopic evaluation) • Change in Robarts Histopathology Index (RHI) score • Proportion of subjects who achieve a 50% reduction in RHI
Exploratory PK/PD endpoints: • Concentration of AMT-101, AMT-101 ADAs, and total IL-10 in mucosal tissue biopsies • Change in high-sensitivity C-reactive protein (hs-CRP) • Change in fecal calprotectin • Change in white blood cell (WBC) count • Change in fecal matrix metallopeptidase-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
Exploratory work productivity endpoint: • Change in Work Productivity and Activity Impairment (WPAI) from baseline
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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 | Yes |
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) | Yes |
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 | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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 |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
United Kingdom |
Netherlands |
Spain |
Switzerland |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 8 |
E.8.9.1 | In the Member State concerned days | 10 |
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 |