| 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 | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
| 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 | 10011401 |
| E.1.2 | Term | Crohn's disease |
| 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 |
To determine the optimal dose of IMU-838 to induce symptomatic remission (based on stool frequency [SF] and abdominal pain [AP], as assessed in the Crohn’s Disease Activity Index [CDAI] patient-reported outcome [PRO]-2) in patients with active Crohn’s disease (CD)
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| E.2.2 | Secondary objectives of the trial |
To determine the optimal dose of IMU-838 to induce endoscopic improvement in patients with active CD.
Further secondary and exploratory objectives
• To evaluate the potential of IMU-838 to induce clinical response and clinical remission
• To evaluate the time course of IMU-838 activity
• To evaluate the durability of response and remission
• To explore the potential of IMU-838 to maintain remission as well as avoid CD relapse
• To evaluate the safety and tolerability of IMU-838 in patients with active CD
• To evaluate trough levels of IMU-838 in patients with active CD
• To assess disease activity markers and biomarkers |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
INDUCTION TREATMENT PHASE
1 Male or female patient, aged 18-80 years
2 Confirmed diagnosis of active luminal CD, at least 3 months before Screening Visit S1
3 SES-CD score of at least 6, or of at least 4 in patients with isolated ileitis (screening ileocolonoscopy and SES-CD score assessed by an in-dependent central reader blinded to center and patient information)
4 At least one aphthous ulcerative lesion or more severe ulcer accessible by ileocolonoscopy (as confirmed by an independent central blinded reader from screening ileocolonoscopy)
5 Full CDAI score ≥220 and ≤450 at Screening Visit S1
6 Average daily very soft or liquid stool frequency score (based on the BSFS) ≥4.0 and/or AP-CDAI score ≥2.0 at Screening Visit S1 (according to retrospective data of the preceding 7 days)
7 Previous treatment failure defined as:
a Patient had an inadequate response with, lost response to, or was in-tolerant to approved or experimental immunomodulators or biologics. A maximum of 3 treatment failures with biologic drugs i.e. anti-tumor necrosis factor alpha antibodies, certolizumab pegol, vedolizumab, natalizumab, ustekinumab, or experimental antibodies, i.e. not approved for the use in CD or not approved but in development for CD, is allowed; or
b Patient had an inadequate response to corticosteroids (a corticosteroidrefractory patient is defined as having active disease despite prednisolone up to 1 mg/kg/day for a period of 4 weeks), was intolerant to corticosteroids, or is corticosteroid dependent (a corticosteroid-dependent patient is defined as i) unable to reduce steroids below the equivalent of prednisolone 10 mg/day [or budesonide be-low 3 mg/day] within 3 months of starting steroids, without recurrent active disease, or ii) who has a relapse within 3 months of stopping steroids.
8 Laboratory values: Neutrophil count >1500 cells/µL (>1.5 x 10^9 cells/L), platelet count
≥100 000/mm3 (≥100 x 10^9/L), serum creatinine <1.5 upper limit of normal (ULN), total bilirubin, alanine aminotransferase, and aspartate aminotransferase <1.5 ULN
9 Female patients
- must be of non-childbearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening Visit S1) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
- if of childbearing potential, must have a negative pregnancy test at Screening Visit S1 (blood test) and at Day 0 before IMP administration (urine test). They must agree not to attempt to become pregnant, not to donate ova and to use a highly effective contraceptive method at the start of the trial (trial consent), during treatment with IMU 838, and for at least 30 days after the last intake of the IMP.
10 Male patients must agree not to father a child or to donate sperm starting at Screening Visit S1, throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients must also
- 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 the IMP and for at least 30 days after the last intake of the IMP, and
- if they have a female partner of childbearing potential, ensure that the partner uses a highly effective contraceptive method as outlined in inclusion criterion 9
- if they have a pregnant partner, use condoms while taking the IMP to avoid exposure of the fetus to the IMP
11 Ability to understand and comply with trial procedures and restrictions
12 Written informed consent
EXTENDED TREATMENT PHASE
1 At least symptomatic response at Week 14, defined as improvement in AP-CDAI or SF CDAI scores of at least 30%, and both scores not worse than at Baseline
CRITERIA FOR SWITCHING FROM BLINDED TREATMENT TO OLE
1 Completion of at least 10 weeks of blinded treatment
2 Completion of a post-baseline ileocolonoscopy (either as EoI or EoBT ileocolonoscopy) in the last 14 weeks before switching to OLE
a if discontinuing the induction treatment phase at Week 10 or be-tween Week 10 and Week 14, a complete EoI visit must be per-formed at the time of discontinuation, including EoI ileocolonos-copy, or
b if discontinuing the extended treatment phase before Week 38, a complete EoBT examination must be performed; however, EoBT ileocolonoscopy will only be required if the EoI ileocolonoscopy was performed more than 14 weeks before the time of discontinuation
3 At least 2 valid assessments of the full CDAI, SF-CDAI and AP-CDAI scores post Baseline: |
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| E.4 | Principal exclusion criteria |
GI CRITERIA
1 Diagnosis of ulcerative colitis, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis
2 High likelihood of requiring bowel surgery during the 38 weeks of the BT period
3 Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
4 Ileorectal anastomosis or ileal-pouch anal anastomosis
5 Celiac disease
6 Presence of intra-abdominal or perianal abscess that is undrained
7 History of subtotal colectomy or imminent need for colectomy (i.e. colectomy is being planned)
8 Malabsorption or short-bowel syndrome
9 History of small bowel or colorectal cancer or gastrointestinal dysplasia (with the exception of dysplasia in polyps that have been removed)
INFECTIOUS DISEASE
10 Clostridium difficile (C. difficile) infection
a Evidence of, or treatment for, C. difficile infection within 30 days before randomization
b Positive C. difficile toxin B stool assay at Screening Visit S1
11 Treatment for intestinal pathogens other than C. difficile within 30 days before randomization
12 Other chronic systemic infections
a History of chronic systemic infections including but not limited to tuberculosis, HIV, HBV, or HCV, within 6 months before Screening Visit S1
b Positive interferon-gamma release assay for Mycobacterium tuberculosis at Screening Visit S1
c Positive HBV surface antigen (HBsAg), hepatitis B core antibody (HBcAb), positive HCV and/or HIV-antigen-antibody (HIV-Ag/Ab) test at Screening Visit S1 (even without detectable virus load in blood)
13 Any live vaccinations within 30 days before randomization except for the influenza vaccine
OTHER MEDICAL HISTORY AND CONCOMITANT DISEASE EXCLUSION CRITERIA
14 Known history of nephrolithiasis or underlying condition with a strong association o nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia
15 Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial
16 Renal impairment i.e. eGFR >60 mL/min/1.73 m²
17 Serum uric acid levels at Screening Visit S1 >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL)
18 History or clinical diagnosis of gout
19 Known or suspected Gilbert syndrome
20 Indirect (unconjugated) bilirubin ≥1.2 x ULN (i.e. ≥1.1 mg/dL) at Screening Visit S1
21 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
22 Use of any IMP within 8 weeks or 5 x the respective half-life before randomization, whichever is longer
23 Use of the following medications within 2 weeks before 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 (at >9 mg/day)
f Oral aminosalicylates (e.g. mesalazines) >4 g/day
24 Use of the following medications within 4 weeks before randomization:
a Use of intravenous corticosteroids
b Use of thiopurines including azathioprine, 6-mercaptopurine and 6-thioguanine
c Use of any rectal or topical aminosalicylates and/or budesonide
25 Use of oral systemic corticosteroids ≤20 mg/day prednisolone equivalent including beclomethasone dipropionate (at ≤5 mg/day) and budesonide (at ≤9 mg/day) unless they have been used at a stable dose for at least 2 weeks before randomization
26 Oral aminosalicylates (e.g. mesalazines) ≤4 g/day unless they have been used at a stable dose for at least 3 weeks before randomization
27 Use of biologics as follows:
a anti-TNFα antibodies (infliximab, adalimumab, golimumab, certolizumab pegol, including their biosimilars, if available) within 4 weeks before randomization
b vedolizumab and ustekinumab within 8 weeks before randomization
28 Use of the DHODH inhibitors leflunomide or teriflunomide within 6 months before randomization
29 Any use of natalizumab (Tysabri™) within 12 months before randomization
30 Use of the following concomitant medications is prohibited at Screening Visit S1 and throughout the duration of the trial:
a any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid
b active treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib
c any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs
d Rosuvastatin at doses >10 mg/day
Please refer to protocol for information on general exclusion criteria and exclusion criteria during OLE period. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Induction treatment phase (BT period)
• Proportion of patients with symptomatic remission at Week 14 i.e. fulfilling the following criteria:
- Remission in AP-CDAI, defined as AP-CDAI score ≤1 and not worse than at Baseline,
and
- Remission in SF-CDAI, defined as SF-CDAI score ≤2.8 and not worse than at Baseline
For the primary analysis, the 45 mg/day IMU-838 will be compared to placebo.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| AP-CDAI and SF-CDAI: screening, pre-dose and week 14 |
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| E.5.2 | Secondary end point(s) |
Induction treatment phase (BT period)
• Proportion of patients achieving endoscopic improvement at Week 14:
- Reduction of the SES-CD by ≥50% versus Baseline, or SES-CD score ≤4 (or in patients with isolated ileitis an SES-CD score ≤2), a reduction of ≥2 points from Baseline, and no ulcer sub-score >1 in any of the 5 segments (ileum, right/transverse/left colon, and rectum)
BT period
• Proportion of patients with endoscopic remission at Weeks 14 and 38
• Change in AP-LPS score and SF-CDAI score from Baseline
Proportion of patients with the primary and the key secondary endpoints for the following comparisons:
- 30 mg/day IMU-838 versus placebo
- 30 mg/day versus 45 mg/day IMU-838
• Proportion of patients in clinical remission (full CDAI) at Weeks 14 and 38
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Induction treatment phase (BT period)
• Proportion of patients achieving endoscopic improvement,
SES-CD: baseline, w14
BT period
• Proportion of patients with endoscopic remission: w14, w38
• AP-LPS score and SF-CDAI score: screening, pre-dose, w1, w2, w6, w10, w14 and w38
• Proportion of patients in clinical remission (full CDAI): screening, pre-dose, w14 and w38 |
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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 | 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 | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 58 |
| 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 |
| Bulgaria |
| Croatia |
| Czech Republic |
| Germany |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovenia |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
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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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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