Clinical Drug Experience Knowledgebase

Criteria

INCLUSION CRITERIA:

Induction phase

Male and female patients, aged 18 - 80 years
UC diagnosed more than 3 months before Screening (Day-30) as documented in the medical chart

Previous treatment failure defined as:

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. anti-tumor necrosis factor α antibodies [infliximab, adalimumab, golimumab and their biosimilars], vedolizumab, or certain experimental antibodies [ustekinumab]); or
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.)

Active disease defined as

a. Mayo stool frequency score of ≥2 at Screening Visit 1 b. Mayo rectal bleeding score of ≥1 at Screening Visit 1 c. 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)

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)
Laboratory values: Neutrophil count >1500 cells/µL, platelet count ≥100 000 /mm3, serum creatinine <1.5 x upper limit of normal (ULN), total bilirubin, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) <1.5 x ULN

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-383 and for at least 3 months after the last dose of study medication

For Poland and the UK the following additional requirement apply:

if male patients have a female partner of childbearing potential, the partner should use a highly effective contraceptive method as outlined in inclusion criterion 7

And additionally, for Poland only:

if male patients have a pregnant partner, they must use condoms while taking study medication to avoid exposure of the fetus to study medication
Ability to understand and comply with study procedures and restrictions
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/End of Induction, 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 assessments)

EXCLUSION CRITERIA:

Gastrointestinal exclusion criteria

Diagnosis of Crohn's disease, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis
Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
History of colectomy with ileorectal anastomosis or ileal-pouch anal anastomosis or imminent need for colectomy (i.e. colectomy is being planned)
Active therapeutically uncontrollable abscess or toxic megacolon
Malabsorption or short bowel syndrome

History of colorectal cancer or colorectal dysplasia (with the exception of dysplasia in polyps which have been removed)

Infectious disease exclusion criteria

Clostridium difficile (C. difficile) infection

Evidence of, or treatment for C. difficile infection within 30 days before first randomization
Positive C. difficile toxin B stool assay during the screening period
Treatment for intestinal pathogens other than C. difficile within 30 days prior to first randomization

Other chronic systemic infections

History of chronic systemic infections including but not limited to tuberculosis, human immunodeficiency virus (HIV), hepatitis B or C, within 6 months before Screening
Positive interferon-gamma release assay (IGRAs) for Mycobacterium tuberculosis at Screening
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

Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine

Other medical history and concomitant disease exclusion criteria

Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia
Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial
Renal impairment i.e. estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m²
Serum uric acid levels at Screening >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL)
History or clinical diagnosis of gout
Known or suspected Gilbert syndrome
Indirect (unconjugated) bilirubin ≥1.2 x ULN at Screening (i.e. ≥ 1.1 mg/dL)

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

Use of any investigational product within 8 weeks or 5 x the respective half-life before first randomization, whatever is longer

Use of the following medications within 2 weeks before first randomization:

Tofacitinib
Methotrexate
Mycophenolate mofetil
Any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus)
Oral systemic corticosteroids >20 mg/day prednisolone equivalent including beclomethasone dipropionate (at >5 mg/day) and budesonide (multi-matrix [MMX] at >9 mg/day)
Oral aminosalicylates (e.g. mesalazines) >4 g/day

Use of the following medications within 4 weeks before first randomization:

Use of intravenous corticosteroids
Use of thiopurines including azathioprine, mercaptopurine and 6-thioguanine
Use of any rectal and topical aminosalicylates and/or budesonide
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
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

Use of biologics as follows:

anti-tumor necrosis factor α antibodies (infliximab, adalimumab, golimumab, including their biosimilars) within 4 weeks before first randomization
vedolizumab and ustekinumab within 8 weeks before first randomization
Use of the DHODH inhibitors leflunomide or teriflunomide within 6 months before first randomization
Any use of natalizumab (Tysabri™) within 12 months before first randomization

Use of the following concomitant medications is prohibited at Screening and throughout the duration of the trial:

any medication known to significantly increase urinary elimination of uric acid, in particular lesinurad (Zurampic™) as well as uricosuric drugs such as probenecid
treatments for any malignancy, in particular irinotecan, paclitaxel, tretinoin, bosutinib, sorafenib, enasidenib, erlotinib, regorafenib, pazopanib and nilotinib
any drug significantly restricting water diuresis, in particular vasopressin and vasopressin analogs
Rosuvastatin at doses ˃10 mg/day

General exclusion criteria

History of, or current serious, severe, or unstable (acute or progressive) physical or mental illness, or any medical condition, including laboratory anomalies or renal or hepatic impairment, that may require treatment or would put the patient in jeopardy if he/she was to participate in the study
Known hypersensitivity to DHODH inhibitors (teriflunomide, leflunomide) or any ingredient of the investigational product
Pregnancy or breastfeeding
History of drug or alcohol abuse during the past year
Concurrent participation in any other clinical trial using an investigational medicinal product or medical device
An employee of an investigator or sponsor or an immediate relative of an investigator

Exclusion criteria for open-label treatment extension arm

Any ongoing, clinically significant treatment-emergent (started during the IMU-838 treatment in the blinded treatment arms) adverse event (AE) or laboratory abnormality (including blood chemistry and urinalysis) as assessed by the investigator *
Significant treatment or study non-compliance during induction and/or maintenance phase (as assessed by the investigator), and/or inability or unwillingness to follow instructions by study personnel as assessed by the investigator

Significant protocol deviations during induction and/or maintenance phase that are assessed by the investigator to negatively affect further patient cooperation in this study

If treatment-emergent AEs are the reason for exclusion from the open-label extension arm, the eligibility can be re-assessed up to 30 days following the last treatment in the blinded treatment arms.