| 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 Objectives:
• To assess the safety, tolerability, systemic exposure, and efficacy of AMT-101 in subjects with chronic pouchitis
• To select an AMT-101 dose for Phase 3
Phase 3 Study Co-primary Objectives:
• To determine the long-term efficacy of AMT-101 on stool frequency in subjects with chronic pouchitis
• To determine the long-term efficacy of AMT-101 on histology in subjects with chronic pouchitis
Safety Objectives
• To assess the safety of AMT-101 in chronic pouchitis
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| E.2.2 | Secondary objectives of the trial |
To demonstrate the efficacy of AMT-101 on:
• stool frequency by the end of the induction period
• histology by the end of the induction period
• the efficacy of AMT-101 on the total number of ulcers or erosions by endoscopic assessment
To evaluate the efficacy of AMT-101 on:
• bowel urgency as measured by the bowel urgency questionnaire
• subject’s impression of change in their symptoms due to pouchitis as measured by the patient global impression of severity (PGI-S) scale
• subject’s global impression of change in their symptoms due to pouchitis using patient global impression of change (PGI-C) scale
• physical and mental activity using the 36-item Short-Form questionnaire (SF-36)
• fatigue using the Functional Assessment of Chronic Illness Therapy - Fatigue Scale Short Form 13a (FACIT-F SF 13a) questionnaire
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Phase 3 inclusion criteria (subjects must meet the following criteria to be randomized into Phase 3; for Phase 2 inclusion/exclusion criteria refer to Protocol Version 4.0):
1. Male and female subjects aged 18 to 75 years, inclusive.
2. History of IPAA for UC completed at least 1 year 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.
“Screening” stool frequency is calculated using the diary entries from 3 consecutive days within the 7 days prior to endoscopy, not including the day of bowel preparation or endoscopy procedure.
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. Active disease despite at least 2 weeks of antibiotic therapy, and
b. ≥ 2 episodes within 1 year prior to or including the screening period treated with antibiotics or other prescription therapy, and/or,
c. Maintenance antibiotic therapy taken continuously for ≥4 weeks immediately prior to the screening endoscopy.
5. Histologic inflammation in the pouch, defined by a Geboes score of ≥ 3.2
6. Women of childbearing potential (WOCBP) are required to use highly effective contraception, including one or more of the following methods, for the duration of the study (i.e., until 4 weeks after last dose of study drug):
• Intrauterine device
• Hormone-based contraceptives (excluding progesterone-only oral contraceptives)
• Total sexual abstinence (if already in line with lifestyle)
• Tubal ligation
• Monogamous intercourse with a sterilized (i.e., vasectomized), or otherwise nonfertile (e.g., castrated) male partner; male must have medical record that confirms sterility
7. WOCBP must have a negative pregnancy test at screening and at the randomization visit prior to the first dose of study drug.
8. Male subjects are required to have a medical record that confirms sterilization (i.e., vasectomized) or otherwise nonfertile (e.g., castrated), or use condoms with spermicide, or abstain from intercourse (if already in line with lifestyle) for the duration of the study.
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 |
1. Known Crohn’s disease (CD) or suspected CD of 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 pouch such as stricture or fistula(e) that preclude evaluation of pouch and terminal ileum.
5. Fecal incontinence due to anal sphincter dysfunction.
6. Pelvic sepsis within 12mths prior to screening.
7. Planned surgery for UC, or other elective surgery within time frame of study.
8. Diverting stoma.
9. Current bacterial or parasitic pathogenic enteric infection, including C.difficile; known infection with hep B or C; known infection with HIV; infection requiring hospitalization or intravenous antimicrobial therapy, or opportunistic infection within 6mths prior to screening; infection requiring antimicrobial therapy within 2wks prior to screening; history of more than 1 episode of herpes zoster or episode of disseminated zoster. Subject with history of hep C infection who has been treated and achieved sustained virology response at 12wks post-treatment (SVR12) is eligible.
10. A +ve diagnostic tuberculosis (TB) test at screening (defined as +ve QuantiFERON test). In cases where QuantiFERON test is indeterminate, subject may have test repeated once and if their 2nd test is -ve they will be eligible. In event 2nd test is also indeterminate, or QuantiFERON is unavailable, investigator has option to perform purified protein derivative (PPD) skin test. If PPD reaction is <5 mm, then subject is eligible. If reaction is ≥5mm, or PPD testing is not done, subject is not eligible. Exception is made for subjects with history of latent TB who are currently receiving treatment for latent TB, will initiate treatment for latent TB before first dose of study treatment, or have documentation of completing appropriate treatment for latent TB within 3yrs prior to first dose of study treatment).
11. Prior biologic use restrictions and exclusions:
a. No more than 60% of enrolled subjects in Phase 3 may have prior failure of biologics for pouchitis.
b. Subjects who have used prior biologic therapies must have discontinued within 12wks or 5 half-lives of screening (or within 4wks if drug levels are undetectable).
12. Use of of following prohibited therapies, except under stated conditions (if applicable):
a. Opioids within 4wks prior to screening.
b. Chronic use (>4wks of continuous use prior to screening) of nonsteroidal anti-inflammatory drugs, except for chronic use of low-dose aspirin (e.g., <100mg/day).
c. Oral 5-aminosalicylate (5-ASA), unless dose is ≤4.8g/day and has been stable for at least 4wks prior to screening.
d. Oral budesonide initiated within 6wks of screening.
e. Other oral corticosteroids at daily doses >20mg prednisone or equivalent, or who started oral corticosteroids within 6wks prior to screening; stable doses ≤20mg prednisone or equivalent for at least 4wks prior to screening are permitted.
f. Rectal compounds.
g. Immunosuppresant therapy (azathioprine, 6-mercaptopurine, methotrexate, cyclosporin) within 8wks prior to screening.
h. Fecal transplant within 12wks prior to screening.
i. Live virus vaccination within 1mth prior to screening.
j. Investigational therapy within 4wks prior to screening.
13. Diagnosed with immune deficiency.
14. History of malignancy, except for basal cell carcinoma, nonmetastatic squamous cell carcinoma of skin, or prior malignancy with curative therapy completed at least 5yrs prior to screening and no recurrence.
15. Clinically meaningful laboratory abnormalities at screening that would affect subject safety, as judged by investigator from local testing.
16. 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 opinion of investigator, might confound study results, pose additional risk to subject, or interfere with subject’s ability to participate fully in study.
17. Current or recent history of alcohol dependence or illicit drug use that, in opinion of investigator, may interfere with subject’s ability to comply with study procedures.
18. Pregnant or lactating females.
19. Surgical procedure requiring general anesthesia within 1mth prior to screening or planned elective surgery during study.
20. Mental or legal incapacitation or history of clinically significant psychiatric disorders at time of screening visit that would impact ability to participate in trial according to investigator.
21. Concurrent participation in other interventional study or received investigational therapy within 1mth prior to screening.
22. Previous exposure to AMT-101.
23. 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 the indicated percent reduction from baseline in stool frequency at Week 52 as an ordinal outcome:
o < 10%
o ≥ 10% and < 20%
o ≥ 20% and < 30%
o ≥ 30% and < 40%
o ≥ 40%
• Proportion of subjects with the indicated Geboes score at Week 52 as an ordinal outcome:
o No improvement
o ≥ 5.1 and an improvement from baseline [i.e., less than baseline]
o ≥ 4.1 and ≤ 5.0 and an improvement from baseline
o ≥ 3.2 and ≤ 4.0 and an improvement from baseline
o ≤ 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) |
Secondary Efficacy Endpoints
• Proportion of subjects with the indicated percent reduction from baseline in stool frequency at Week 12 as an ordinal outcome:
o < 10%
o ≥10% and < 20%
o ≥20% and < 30%
o ≥30% and < 40%
o ≥40%
• Proportion of subjects with the indicated Geboes score at Week 12 as an ordinal outcome:
o No improvement
o ≥ 5.1 and an improvement from baseline [i.e., less than baseline]
o ≥ 4.1 and ≤ 5.0 and an improvement from baseline
o ≥ 3.2 and ≤ 4.0 and an improvement from baseline
o ≤ 3.1
• Proportion of subjects with the indicated change from baseline in the total number of ulcers or erosions as an ordinal outcome at Week 52
o No improvement
o > 0 and < 10%
o ≥10% and < 20%
o ≥20% and < 30%
o ≥30% and < 40%
o ≥40%
• Proportion of subjects with indicated percent change from baseline in the total number of ulcers or erosions as an ordinal outcome at Week 12
o No improvement
o > 0 and < 10%
o ≥10% and < 20%
o ≥20% and < 30%
o ≥30% and < 40%
o ≥40%
• Proportion of subjects with no bowel urgency at Week 12
• Proportion of subjects with no bowel urgency at Week 52
• Mean change from baseline in PGI-S score at Week 12
• Mean change from baseline in PGI-S score at Week 52
• Mean of PGI-C score at Week 12
• Mean of PGI-C score at Week 52
• Mean change from baseline in the physical component score of the SF-36 score at Week 52
• Mean change from baseline in the mental component score of the SF-36 score at Week 52
• Mean change from baseline in FACIT-F SF 13a score at Week 52
Health Outcome Endpoints
• Mean change from baseline in total score of IBDQ
• Mean change from baseline in EQ-5D index score
• Mean change from baseline in EQ-5D visual analog scale (VAS)
• Mean change from baseline in WPAI score (absenteeism, presenteeism, overall work productivity impairment, activity impairment)
•Mean change from baseline in PGI-S score at Week 2
• Mean PGI-C score at Week 2
Exploratory efficacy, PK/PD endpoints are described in the body of the protocol.
Safety Endpoints
Both Phase 2 and Phase 3:
• Proportion of subjects with treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (SAEs), and discontinuation due to TEAEs
• Change from baseline in laboratory parameters
• Change from baseline in vital signs
• Change from baseline in electrocardiogram (ECG) parameters
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Weeks 2, 6, 10, 12, 16, 24, 32, 40 and 52 |
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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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| Australia |
| Canada |
| Israel |
| United States |
| Finland |
| France |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Italy |
| Belgium |
| Denmark |
| Hungary |
| Ireland |
| United Kingdom |
| Serbia |
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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