| 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 |
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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 |
The primary objective is to determine the optimal dose of IMU-838 to induce symptomatic remission and endoscopic healing in patients with moderate-to-severe ulcerative colitis (UC)
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| E.2.2 | Secondary objectives of the trial |
The secondary objective are:
To determine the optimal dose of IMU-838 to maintain clinical benefits in patients with moderate-to-severe UC
• To evaluate the effects of IMU-838 on clinical and endoscopic endpoints in patients with moderate-to-severe UC
• To evaluate the time course of activity and effects of IMU-838
• To evaluate the safety and tolerability of IMU-838 in patients with moderate-to-severe UC
• To evaluate exploratory biomarkers, disease activity biomarkers, and pharmacodynamic (PD) effects of IMU-838
• To evaluate population pharmacokinetics (PK) and plasma trough levels of IMU-838 throughout the induction period
• To evaluate single dose PK at Week 50 for a subpopulation of patients with moderate-to-severe UC receiving 30 mg of IMU-838
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Induction phase
1. Male and female patients, aged 18 - 80 years
2. UC diagnosed more than 3 months before Screening (Day -30) as documented in the medical chart
3. Previous treatment failure defined as:
a. Patient had an inadequate response with, lost response to, or was intolerant to approved or experimental immunomodulators (azathioprine, 6-mercaptopurine, 6-thioguanine, methotrexate, or tofacitinib) or biologics (no more than 2 treatment failures with biologic drugs i.e. infliximab, adalimumab, golimumab and their biosimilars, vedolizumab, or ustekinumab); or
b. Patient had an inadequate response to, was intolerant to, or is corticosteroid dependent (corticosteroid-dependent patients are defined as i) unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting steroids, without recurrent active disease, or ii) who have a relapse within 3 months of stopping steroids)
4. Active disease defined as
a. Mayo stool frequency score of ≥2 at Screening Visit 1
a. Mayo rectal bleeding score of ≥1 at Screening Visit 1
b. modified Mayo endoscopy subscore of ≥2 at the screening flexible sigmoidoscopy (endoscopy assessed by an independent central reader blinded to screening center and patient information)
5. Endoscopic appearance typical for UC and extending >15 cm from the anal verge as confirmed by an independent central reader (blinded to screening center and patient information)
6. Laboratory values: Neutrophil count >1500 cells/µL (> 1.5 x 10^9/L), platelet count ≥100 000/mm3 (≥ 100 10^9/L), serum creatinine <1.5 x upper limit of normal (ULN), total bilirubin, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) <1.5 x ULN
7. Female patients must
a. Be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening) or post-menopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
b. If of child-bearing potential, must have a negative pregnancy test at Screening (blood test) and before the first study drug administration (Day 0 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method 2 months before Screening, during treatment with IMU-838, and at least 3 months after the last dose of study therapy
Highly effective forms of birth control are those with a failure rate less than 1% per year and include:
− oral, intravaginal, or transdermal combined (estrogen and progestogen containing) hormonal contraceptives associated with inhibition of ovulation
− oral, injectable, or implantable progestogen-only hormonal contraceptives associated with inhibition of ovulation
− intrauterine device or intrauterine hormone-releasing system
− bilateral tubal occlusion
− vasectomized partner (i.e. the patient’s male partner has undergone effective surgical sterilization before the female patient entered the clinical trial and he is the sole sexual partner of the female patient during the clinical trial)
− sexual abstinence (acceptable only if it is the patient’s usual form of birth control/lifestyle choice)
8. Male patients must agree not to father a child or to donate sperm starting at Screening and throughout the clinical trial and for 3 months after the last dose of study medication. Male patients must also either
-abstain from sexual intercourse with a female partner (acceptable only if it is the patient’s usual form of birth control/lifestyle choice), Or
-use adequate barrier contraception during treatment with IMU-838 and for at least 3 months after the last dose of study medication
9. Ability to understand and comply with study procedures and restrictions
10. The patient is legally competent, has been informed of the nature, the scope and the relevance of the study, voluntarily agrees to participation and the study’s provisions and has duly signed the informed consent form
MAINTENANCE PHASE
1. Symptomatic remission achieved at Week 10 or Week 22 of the induction phase
Open-label treatment extension arm
1. Patient is in the induction phase, had received at least 6 weeks of blinded study treatment and completed the sigmoidoscopy (incl. biopsy) regularly scheduled at Week 10/EoI, and has neither reached symptomatic remission nor symptomatic response
Or
Patient is in the extended induction phase, had completed all Week 10 assessments, and has not reached symptomatic remission during or at the end of the extended induction phase,
Or
Patient is in the maintenance phase and discontinues from the maintenance phase due to
symptomatic UC relapse or other reasons with a flexible sigmoidoscopy performed at discontinuation (if the previous sigmoidoscopy had been performed more than 4 weeks before discontinuation)
Or
Patient has completed the maintenance phase as scheduled (including all Week 50 assesments) |
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| E.4 | Principal exclusion criteria |
Gastrointestinal exclusion criteria:
1. Diagnosis of Crohn’s disease, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis
2. Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
3. History of colectomy with ileorectal anastomosis or ileal-pouch anal anastomosis or imminent need for colectomy (i.e. colectomy is being planned)
4. Active therapeutically uncontrollable abscess or toxic megacolon
5. Malabsorption or short bowel syndrome
6. History of colorectal cancer or colorectal dysplasia (with the exception of dysplasia in polyps which have been removed)
Infectious disease exclusion criteria
7. Clostridium difficile (C. difficile) infection
o Evidence of, or treatment for C. difficile infection within 30 days before first randomization
o Positive C. difficile toxin B stool assay during the screening period
8. Treatment for intestinal pathogens other than C. difficile within 30 days prior to first randomization
9. Other chronic systemic infections
o History of chronic systemic infections including but not limited to tuberculosis, HIV, hepatitis B or C, within 6 months before Screening
o Positive interferon-gamma release assay (IGRAs) for Mycobacterium tuberculosis at Screening
o Positive HBsAg (hepatitis B virus surface antigen), HBcAb (hepatitis B core antibody), positive hepatitis C virus and/or HIV-antigen-antibody (HIV-Ag/Ab) test at Screening
10. Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine
Other medical history and concomitant disease exclusion criteria
11. Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia
12. Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial
13. Renal impairment i.e. estimated glomerular filtration rate ≤60 mL/min/1.73m²
14. Serum uric acid levels at Screening >1.2 x ULN (women: >6.8 mg/dL, men: >8.4 mg/dL)
15. History or clinical diagnosis of gout
16. Known or suspected Gilbert syndrome
17. Indirect (unconjugated) bilirubin ≥1.2 x ULN at Screening (i.e. ≥ 1.1 mg/dL)
18. Concurrent malignancy or prior malignancy within the previous 10 years except for the following: adequately-treated non-melanoma skin cancer and adequately-treated cervical cancer
Therapy exclusion criteria:
19. Use of any investigational product within 8 weeks or 5 x the respective half-life before first randomization, whatever is longer
20. Use of the following medications within 2 weeks before first randomization:
a. Tofacitinib
b. Methotrexate,
c. Mycophenolate mofetil
d. Any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus)
e. Oral systemic corticosteroids >20 mg/day prednisolone equivalent including beclomethasone dipropionate (at >5 mg/day) and budesonide (multi-matrix [MMX] at >9 mg/day)
f. Oral aminosalicylates (e.g. mesalazines) >4 g/day
21. Use of the following medications within 4 weeks before first randomization:
a. intravenous corticosteroids
b. thiopurines including azathioprine, mercaptopurine and 6-thioguanine
c. any rectal and topical aminosalicylates and/or budesonide
22. Use of oral systemic corticosteroids ≤20 mg/day prednisolone equivalent including beclomethasone dipropionate (at ≤5 mg/day) and budesonide (MMX at ≤9 mg/day) unless they have been used for at least 4 weeks before first randomization and at a stable dose for at least 2 weeks before first randomization
23. Oral aminosalicylates (e.g. mesalazines) ≤4 g/day unless they have been used for at least 6 weeks and with a stable dose for at least 3 weeks before first randomization
24. Use of biologics as follows:
a. anti-tumor necrosis factor α antibodies (infliximab, adalimumab, golimumab, including their biosimilars) within 4 weeks before first randomization
b. vedolizumab and ustekinumab within 8 weeks before first randomization
25. Use of the DHODH inhibitors leflunomide or teriflunomide within 6 months before first randomization
26. Any use of natalizumab (Tysabri™) within 12 months before first randomization
27. Use of the following concomitant medications is prohibited at Screening and throughout the duration of the trial:
o any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid
o treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib.
o any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs
criteria
o Rosuvastatin at doses >10 mg/day
Please refer to protocol for additional information |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint is:
Efficacy
Induction phase
• Composite endpoint: Proportion of patients with both, symptomatic remission and endoscopic healing at Week 10
All patients (both, Enrollment Period 1 and Enrollment Period 2 patients) who were randomized to 30 mg/day and 45 mg/day IMU-838 will be used for the assessment of the primary efficacy endpoint (see Section 16.4 of protocol for further information).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Proportion of patients with both, symptomatic remission and endoscopic healing at Week 10
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| E.5.2 | Secondary end point(s) |
Secondary endpoint is:
Efficacy
Induction phase and extended induction phase
• Proportion of patients with both symptomatic remission and endoscopic healing at Week 10 (all individual IMU-838 doses will be compared with one another and to placebo)
• Proportion of patients achieving symptomatic remission during the induction phase (including extended induction phase)
• Time to achieving symptomatic remission within the induction/extended induction phase
• Proportion of patients with clinical response at Week 10
• Proportion of patients with endoscopic healing at Week 10
• Proportion of patients with symptomatic response during the induction phase (including extended induction phase)
• Time course of Mayo scores (full score, partial score, PRO-2 score) over 10 or 22 weeks and changes from Baseline
• Time course of disease activity biomarkers (fCP and CRP)
Maintenance phase
• Proportion of patients in symptomatic remission by visit up to Week 50
• Proportion of patients in durable symptomatic remission up to Week 50
• Time course of Mayo PRO-2 score until Week 50
• Time to symptomatic UC relapse
• Proportion of patients without symptomatic UC relapse until Week 50
• Time course of disease activity biomarkers (fCP and CRP)
• Proportion of patients with endoscopic healing at Week 50
• Proportion of patients with microscopic healing at Week 50
• Corticosteroid-free remission at Week 50 in patients receiving corticosteroids at Baseline Open-label treatment extension arm
• Proportion of patients with symptom control
• Time course of disease activity biomarkers (fCP and CRP)
Safety
• Incidence and severity of AEs
• Physical examination, body weight, and vital signs*
• Electrocardiogram (12-lead ECG)*
• Safety laboratory: hematology, clinical chemistry including liver function, coagulation parameters, urinalysis
• miR-122 expression (before first dose and 24 hours after first dose)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Efficacy:
Induction Phase:
Proportion of patients with both symptomatic remission and endoscopic healing at Week 10.
Maintenance Phase:
• Proportion of patients in symptomatic remission by visit up to Week 50
• Proportion of patients in durable symptomatic remission up to Week 50 |
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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 | No |
| 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) | 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 | 3 |
| 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 | 59 |
| 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 |
| Bosnia and Herzegovina |
| North Macedonia |
| Ukraine |
| Belarus |
| Russian Federation |
| Serbia |
| United Kingdom |
| United States |
| Belgium |
| Bulgaria |
| Croatia |
| Czechia |
| Germany |
| Netherlands |
| Poland |
| Portugal |
| Romania |
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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 | 10 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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