Phase 2 Dose-finding IMU-838 for Ulcerative Colitis

Study Overview
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Brief Summary
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This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding study to evaluate the efficacy and safety of IMU-838 for induction and maintenance therapy with an option for open-label treatment extension in moderate-to-severe ulcerative colitis (CALDOSE-1).

Detailed Description
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The investigational medicinal product (IMP) IMU-838 (vidofludimus calcium) is a new compound that selectively inhibits the human enzyme dihydroorotate dehydrogenase (DHODH). Dihydroorotate dehydrogenase plays a major role in the de-novo pyrimidine synthesis and is specifically expressed at high levels in proliferating or activated lymphocytes. Resting lymphocytes satisfy their pyrimidine requirements through a DHODH-independent salvage pathway. Thus, IMU-838-mediated DHODH inhibition selectively affects activated, rapidly proliferating lymphocytes. The metabolic stress secondary to DHODH inhibition leads to a reduction of pro-inflammatory cytokine release including interleukin (IL)-17 (IL-17A and IL-17F) and interferon gamma (IFNγ), and to an increased apoptosis in activated lymphocytes. This is a phase 2, multicenter, randomized, double-blind, and placebo-controlled trial in patients with moderate-to-severe UC with an option for open-label treatment extension. The study comprises a blinded induction phase to establish the optimal dose of IMU-838 to induce response and remission, a blinded maintenance phase to evaluate the potential of IMU-838 to maintain remission until Week 50, and an open-label treatment extension arm for all patients who discontinue the blinded phase as scheduled or prematurely, subject to certain restrictions. A subset of patients will undergo a pharmacokinetic (PK) period at the start of the open-label period to establish a full single-dose PK profile.

Official Title
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A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled, Dose-finding Study to Evaluate the Efficacy and Safety of IMU-838 for Induction and Maintenance Therapy in Moderate-to-severe Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: IMU-838
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg IMU-838 (Induction)<br>Two 5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment. | Drug: IMU-838<br>* IMU-838 tablet<br>* Other names: vidofludimus calcium;|
| Experimental: 30 mg IMU-838 (Induction)<br>Two 15 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment. | Drug: IMU-838<br>* IMU-838 tablet<br>* Other names: vidofludimus calcium;|
| Experimental: 45 mg IMU-838 (Induction)<br>Two 22.5 mg tablets once daily of IMU-838 for 10 to 22 weeks depending on symptomatic remission at Weeks 10 or 22. Patients will receive only half of their assigned full dose during the first week of treatment. | Drug: IMU-838<br>* IMU-838 tablet<br>* Other names: vidofludimus calcium;|
| Placebo Comparator: placebo (during induction)<br>The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging. | Drug: Placebo<br>* Tablets manufactured to mimic IMU-838 tablets<br>* Other names: Placebo (for IMU-838);|
| Experimental: 10 mg IMU-838 (Maintenance)<br>Two 5 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse. | Drug: IMU-838<br>* IMU-838 tablet<br>* Other names: vidofludimus calcium;|
| Experimental: 30 mg IMU-838 (Maintenance)<br>Two 15 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse. | Drug: IMU-838<br>* IMU-838 tablet<br>* Other names: vidofludimus calcium;|
| Placebo Comparator: placebo (during maintenance)<br>The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging. Patients who have received placebo during the induction phase will be 're-randomized' to continue to receive placebo (in a blinded fashion). | Drug: Placebo<br>* Tablets manufactured to mimic IMU-838 tablets<br>* Other names: Placebo (for IMU-838);|
| Experimental: 30 mg IMU-838 (Open-label)<br>Two 15 mg tablets once daily of IMU-838 or one 30 mg tablet IMU-838 once daily for up to 10 years and up to 3 years in UK sites | Drug: IMU-838<br>* IMU-838 tablet<br>* Other names: vidofludimus calcium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic remission and endoscopic healing | 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 will be used for the assessment of the primary efficacy endpoint | Week 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Symptomatic remission and endoscopic healing at different doses | 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) | Week 10 | 
| Symptomatic remission during induction | Proportion of patients achieving symptomatic remission during the induction phase (including extended induction phase) | 22 weeks | 
| Time to achieving symptomatic remission | Time to achieving symptomatic remission within the induction/extended induction phase | 22 weeks | 
| Proportion of patients with clinical response | Proportion of patients with clinical response at Week 10 | 10 weeks | 
| Proportion of patients with endoscopic healing | Proportion of patients with endoscopic healing at Week 10 | Week 10 | 
| Proportion of patients with symptomatic response | Proportion of patients with symptomatic response during the induction phase (including extended induction phase) | 22 weeks | 
| Full Mayo Score | Change in full Mayo Score compared to baseline at Week 10 | Week 10 | 
| Partial Mayo Score | Change in partial mayo score over 10 or 22 weeks | Up to Week 22 | 
| Patient Reported Outcome (PRO)-2 Mayo Score | Change in PRO-2 mayo score over 10 or 22 weeks | Up to Week 22 | 
| Fecal calprotectin (fCP) | Change in the presence of biomarker fCP in stool samples | Changes from Baseline over 10 or 22 weeks | 
| C-reactive protein (CRP) | Change in the presence of biomarker CRP in blood samples | Changes from Baseline over 10 or 22 weeks | 
| Safety: Adverse Events | Incidence and Severity of AEs | up to Week 50 | 
| Safety: Number of participants with clinically significant findings during physical examination | The emergence of any clinically significant findings compared to screening will be captured during the induction and maintenance phases | up to Week 50 | 
| Safety: body weight | Changes in body weight during the induction and maintenance phases | up to Week 50 | 
| Safety: blood pressure | Changes in blood pressure (mm Hg) during the induction and maintenance phases | up to Week 50 | 
| Safety: heart rate | Changes in heart rate (beats per minute) during the induction and maintenance phases | up to Week 50 | 
| Safety: 12-lead electrocardiogram (ECG) | Number of patients with clinically significant changes in ECG | up to Week 50 | 
| Safety: Hematology | Number of participants with abnormal hematology laboratory values | up to Week 50 | 
| Safety: Blood Chemistry | Number of participants with abnormal blood chemistry laboratory values | up to Week 50 | 
| Safety: Coagulation | Number of participants with abnormal coagulation laboratory values | up to Week 50 | 
| Safety: Urinalysis | Number of participants with abnormal urinalysis laboratory values | up to Week 50 | 
| Safety: Micro ribonucleic acid expression | Micro ribonucleic acid-122 (miR-122) expression (before first dose and 24 hours after first dose) | pre-dose and 24 hours post-dose | 
| PK: IMU-838 trough level | Measurement of pre-dose (trough) blood plasma levels of IMU-838 throughout the induction period | up to Week 10 | 
| PK: IMU-838 plasma level | Measurement of post-dose blood plasma levels of IMU-838 at Week 2 | Week 2 | 
| PK: area under the drug concentration-time curve (AUC) from time zero to 24 hours (AUC0-24h) | Single-dose PK measurement of AUC0-24h in a subset of patients in the open-label phase | pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose | 
| PK: AUC time zero to last measurable concentration (AUC0-t) | Single-dose PK measurement of AUC0-t in a subset of patients in the open-label phase | pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose | 
| PK: AUC time zero to infinity (AUC0-inf) | Single-dose PK measurement of AUC0-inf in a subset of patients in the open-label phase | pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose | 
| PK: maximum plasma concentration (Cmax) | Single-dose PK measurement of Cmax in a subset of patients in the open-label phase | pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose | 
| PK: time to Cmax (Tmax) | Single-dose PK measurement of Tmax in a subset of patients in the open-label phase | pre-dose, 1, 2, 3, 4, 5, 6 hours post PK dose; 24 hours post PK dose; 48 hours post PK dose; 72 hours post PK dose | 
| Maintenance Phase: Proportion of patients with symptomatic response | Proportion of patients in symptomatic remission by visit up to Week 50 | up to Week 50 | 
| Maintenance Phase: Mayo PRO-2 score | Time course of Mayo PRO-2 score until Week 50 | Week 50 | 
| Maintenance Phase: Time to relapse | Time to symptomatic ulcerative colitis (UC) relapse | up to Week 50 | 
| Maintenance Phase: Proportion of patients without relapse | Proportion of patients without symptomatic UC relapse until Week 50 | Week 50 | 
| Maintenance Phase: fCP | Change in the presence of biomarker fCP in stool samples | up to Week 50 | 
| Maintenance Phase: CRP | Change in the presence of biomarker CRP in blood samples | up to Week 50 | 
| Maintenance Phase: Proportion of patients with endoscopic healing | Proportion of patients with endoscopic healing at Week 50 | Week 50 | 
| Maintenance Phase: Proportion of patients with microscopic healing | Proportion of patients with microscopic healing at Week 50 | Week 50 | 
| Maintenance Phase: corticosteroid-free remission | Corticosteroid-free remission at Week 50 in patients receiving corticosteroids at Baseline | Week 50 | 
| Open-label Phase: symptom control | Proportion of patients with symptom control | Up to 10 years | 
| Open-label Phase: fCP | Change in the presence of biomarker fCP in stool samples | Up to 10 years | 
| Open-label Phase: CRP | Change in the presence of biomarker fCP in blood samples | Up to 10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ulcerative Colitis, IMU-838, vidofludimus calcium