Phase 2 Dose-finding IMU-838 for Ulcerative Colitis (CALDOSE-1)

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

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).

Study Overview

• Status: Terminated
• Conditions: Ulcerative Colitis
• Intervention / Treatment: Drug: IMU-838; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 263
• Phase: Phase 2

Contacts and Locations

Study Locations

• Albania
  • Durres, Albania, 2001
    • Durres Regional Hospital
  • Shkoder, Albania, 4001
    • Regional Hospital of Shkoder
  • Tirana, Albania, 1000
    • University Hospital Center Mother Teresa
• Belarus
  • Gomel, Belarus, 246029
    • Gomel Regional Clinical Hospital
  • Gomel, Belarus, 246040
    • Republican Scientific and Practical Center for Radiation Medicine and Human Ecology
  • Vitebsk, Belarus, 210009
    • Vitiebsk State Order of Peoples' Friendship Medical University
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina, 78000
    • University Clinical Centre of the Republic of Srpska, Internal Medicine Clinic, Department of Gastroenterology and Hepatology
  • Mostar, Bosnia and Herzegovina, 88000
    • University Clinical Hospital Mostar, Internal Medicine Clinic, Department of Gastroenterology
• Bulgaria
  • Blagoevgrad, Bulgaria, 2700
    • Multiprofile Hospital for Active Treatment Blagoevgrad AD
  • Byala, Bulgaria, 187100
    • Mhat Byala
  • Kazanlak, Bulgaria, 6100
    • Multiprofile Hospital for Active Treatment "Dr. Hristo Stambolski" EOOD
  • Pleven, Bulgaria, 5800
    • Medical Center "Medconsult Pleven" OOD
  • Pleven, Bulgaria, 5800
    • Medical Center Exacta Medica
  • Plovdiv, Bulgaria, 4002
    • University Multiprofile Hospital for Active Treatment "Sveti Georgi" EAD, Plovdiv, Gastroenterology clinic
  • Sofia, Bulgaria, 1510
    • Medical Center "Hera" EOOD
  • Sofia, Bulgaria, 1680
    • Diagnostic-Consulting Center "Convex" EOOD
• Croatia
  • Bjelovar, Croatia, 43000
    • General Hospital Bjelovar
  • Osijek, Croatia, 31000
    • Clinical Hospital Center Osijek
  • Rijeka, Croatia, 51000
    • Clinical Hospital Center Rijeka
  • Split, Croatia, 21000
    • Clinical Hospital Center Split
  • Vukovar, Croatia, 32000
    • General Hospital Vukovar
  • Zagreb, Croatia, 10000
    • Clinical Hospital Center Zagreb
  • Zagreb, Croatia, 10000
    • Clinical Hospital Dubrava
  • Zagreb, Croatia, 10000
    • Polyclinic Solmed Zagreb
  • Zagreb, Croatia, 21000
    • Clinical Hospital Center Split
• Czechia
  • Havířov, Czechia, 73601
    • Asclepiades - Interna a gastroenterologie s.r.o. - Havířov
  • Hradec Králové, Czechia, 50012
    • Hepato-Gastroenterologie HK, s.r.o. Poliklinika III
  • Ostrava - Třebovice, Czechia, 72200
    • Artroscan s.r.o.
  • Praha, Czechia, 10100
    • FaraCol s.r.o. - Prague
  • Praha, Czechia, 14000
    • MEDICON a.s. - Poliklinika Budějovická Gastroenterologie
  • Praha, Czechia, 14300
    • Klinika ResTrial
  • Praha, Czechia, 17004
    • Všeobecná fakultní nemocnice v Praze IV. interní klinika VFN a 1. LF UK
• Georgia
  • Kutaisi, Georgia, 4600
    • Academician Z.Tskhakaia West Georgia National Center of Interventional Medicine
  • Tbilisi, Georgia, 0159
    • LTD Unimedi Kakheti - Caraps Medline
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC, locatie AMC
  • Dordrecht, Netherlands, 3318 AT
    • Albert Schweitzer Hospital
  • Tilburg, Netherlands, 5022 GC
    • Elisabeth-TweeSteden hospital
• North Macedonia
  • Skopje, North Macedonia, 1000
    • City General Hospita 8th September
  • Skopje, North Macedonia, 1131
    • University Clinic for Hematology - Skopje - Macedonian Hematology Association
• Poland
  • Bochnia, Poland, 32700
    • Centrum Usług Medycznych MaxMed
  • Gdynia, Poland, 81338
    • Centrum Medyczne Pratia Gdynia
  • Karczew, Poland, 05480
    • Centrum Medyczne Endo-med Sp. z o.o.
  • Katowice, Poland, 40748
    • Vita Longa Sp. z o.o.
  • Kłodzko, Poland, 57300
    • GLOBE Badania Kliniczne Sp. z o.o.
  • Lublin, Poland, 20954
    • Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie Oddział Gastroenterologii
  • Nowy Targ, Poland, 34400
    • Zakład leczniczy ALLMEDICA BADANIA KLINICZNE Sp. z o.o. Sp. K.
  • Olsztyn, Poland, 10117
    • Etyka Osrodek Badan Klinicznych
  • Piła, Poland, 64920
    • Ars Medical - Szpital, Ars Medical - Ambulatorium
  • Poznań, Poland, 60529
    • Solumed Centrum Medyczne
  • Poznań, Poland, 61485
    • Niepubliczny Zakład Opieki Zdrowotnej Centrum Medyczne HCP - Lecznictwo Stacjonarne
  • Sopot, Poland, 81756
    • ENDOSKOPIA Sp. z o.o.
  • Warszawa, Poland, 02-884
    • Klinika Medifem
  • Warszawa, Poland, 02679
    • Centrum Badawcze Współczesnej Terapii, Prywatny Gabinet Lekarski dr Anna Bochenek-Mularczyk
  • Wroclaw, Poland, 53149
    • Przychodnia Vistamed
  • Wrocław, Poland, 54204
    • Centrum Medyczne OMNI Clinic Sp. z o.o. Spółka Komandytowa
  • Łódz, Poland, 91034
    • Centrum Medyczne Med-Gastr Sp. z o.o. Spółka Komandytowa
  • Łódź, Poland, 91211
    • Salve Medica Sp. z o.o. Spółka Komandytowa
• Portugal
  • Coimbra, Portugal, 3000-075
    • Centro Hospitalar e Universitário de Coimbra, EPE - Hospitais da Universidade de Coimbra
  • Guimarães, Portugal, 4835-044
    • Hospital da Senhora da Oliveira - Guimarães, EPE
  • Santa Maria da Feira, Portugal, 4520-211
    • Centro Hospitalar de Entre o Douro e Vouga, EPE - Hospital Sao Sebastiao
• Romania
  • Bucharest, Romania, 10719
    • S.C. MEDLIFE S.A., Sectia Gastroenterologie
  • Bucharest, Romania, 20125
    • Spitalul Clinic Colentina, Sectia Gastroenterologie
  • Bucharest, Romania, 22328
    • Institutul Clinic Fundeni, Sectia Clinica Gastroenterologie III
  • Timisoara, Romania, 300002
    • S.C. Cabinet Particular Policlinic Algomed SRL, Specialitatea Gastroenterologie
• Russian Federation
  • Kazan, Russian Federation, 420012
    • Kazan State Medical University
  • Krasnodar, Russian Federation, 350072
    • SEI HPE "Kuban State Medical University" of MoH and SD, CBHS Regional Clinical Hospital No.2
  • Moscow, Russian Federation, 123098
    • Federal Medical Biophysical Center n.a. Burnazyan
  • Moscow, Russian Federation, 129110
    • Clinical Research Institution of Moscow Region named after M. F. Vladimirsky
  • Moscow, Russian Federation, 119435
    • Central Clinical Hospital of the Russian Academy of Sciences
  • Novosibirsk, Russian Federation, 630007
    • Novosibirskiy Gastrocenter, LLC
  • Saint Petersburg, Russian Federation, 196143
    • Research Center Eco-Safety, LLC
  • Saint Petersburg, Russian Federation, 191015
    • FSBEI HE "Military Medical Academy n.a. S.M. Kirov" under the Ministry of Defence of Russian Federation
  • Saint Petersburg, Russian Federation, 195257
    • Hospital of Saint Martyr Elizaveta
  • Saint Petersburg, Russian Federation, 196620
    • Gastroenterological Center "Expert" LLC
  • Saint Petersburg, Russian Federation, 197101
    • Saint Petersburg State Medical University named after I.P. Pavlov
  • Sochi, Russian Federation, 354207
    • City Hospital No. 5 - Sochi
  • Tomsk, Russian Federation, 634050
    • Siberian State Medical University
  • Tomsk, Russian Federation, 634063
    • Regional State Autonomous Healthcare Institution "Tomsk Regional Clinical Hospital"
• Serbia
  • Belgrade, Serbia, 11000
    • Clinic for gastroenterohepatology
  • Belgrade, Serbia, 11070
    • Clinical Hospital Center Zemun
  • Belgrade, Serbia, 11080
    • University Hospital Center Bezaniska Kosa
  • Kragujevac, Serbia, 34000
    • Clinical Center Kragujevac
  • Leskovac, Serbia, 16000
    • General Hospital Leskovac
  • Nis, Serbia, 18000
    • Clinical Center Nis
  • Zrenjanin, Serbia, 34000
    • General Hospital Djordje Joanovic, Internal Deases Department, Gastroenterology
• Spain
  • Huelva, Spain
    • Hospital Juan Ramón Jimenez
• Turkey
  • Fatih, Turkey, 34093
    • Bezmiâlem Vakıf Üniversitesi
  • Fatih, Turkey, 34093
    • Istanbul Universitesi Istanbul Tip Fakultesi Gastroenteroloji Bilim Dali
  • Trabzon, Turkey, 61080
    • Karadeniz Teknik Üniversitesi Tip Fakültesi
• Ukraine
  • Dnipro, Ukraine, 49005
    • Public Enterprise "Dnipropetrovsk regional clinical hospital named after I.I. Mechnikova", Department of Gastroenterology (Hepatology)
  • Ivano-Frankivs'k, Ukraine, 76008
    • MNPE "Regional Clinical Hospital of Ivano-Frankivsk Regional Council", Gastroenterology Department, SHEI "Ivano-Frankivsk National Medical University", Chair of Internal Medicine #1
  • Ivano-Frankivs'k, Ukraine, 76018
    • Ivano-Frankivsk City Clinical Hospital No. 1
  • Kharkiv, Ukraine, 61037
    • Municipal Non-profit Enterprise "City Clinical Hospital #2 named after prof. O.O. Shalimova", of Kharkiv City Council, Proctology Department
  • Kharkiv, Ukraine, 61201
    • Municipal Non-profit Enterprise of Kharkiv Regional Council "Regional Clinical Hospital", Gastroenterology Department
  • Kropyvnytskyi, Ukraine, 25006
    • Private Enterprise Private Manufacturing Firm "Acinus", Treatment and diagnostic Centre
  • Kyiv, Ukraine, 01001
    • Medical Center Medical Clinic Blagomed LLC
  • Kyiv, Ukraine, 01030
    • Kyiv City Clinical Hospital #18, Proctology Department, National Medical University named after O.O.Bogomolets, Chair of Surgery #1
  • Kyiv, Ukraine, 02091
    • Kyiv City Clinical Hospital #1, Therapeutics Department #2
  • Kyiv, Ukraine, 02132
    • Medical Centre of Limited Liability Company "Medical Centre "Dopomoga plus""
  • Kyiv, Ukraine, 03680
    • Shalimov's National Institute of surgery and transplantation
  • Kyiv, Ukraine, 04050
    • Medical Centre of Limited Liability Company "Medical Centre "Consilium Medical", clinico-consultation department
  • Kyiv, Ukraine, 04073
    • Kyiv Regional Clinical Hospital No 2
  • Lutsk, Ukraine, 43000
    • Volyn Regional Clinical Hospital
  • Lviv, Ukraine, 79010
    • Municipal Non-profit Enterprise of Lviv Regional Council "Lviv Regional Clinical Hospital", proctology department, Danylo Galytsky Lviv National Medical University, Chair of Surgery #1
  • Mykolaiv, Ukraine, 08711
    • KARDIOKOM Ltd.
  • Uzhhorod, Ukraine, 88018
    • Transcarpathian Regional Clinical Hospital named after Andriy Novaka, gastroenterology department
  • Vinnytsia, Ukraine, 20128
    • Municipal Non-profit Enterprise "Vinnytsia Regional Clinical Hospital named after M.I. Pyrogova of Vinnytsia Regional Council, Regional Specialized Clinical Gastroenterological Center,
  • Vinnytsia, Ukraine, 21029
    • Municipal Non-profit Enterprise "Vinnytsia City Clinical Hospital #1, Gastroenterology Department, Vinnytsia National Medical University named after M.I.Pyrogova, Chair of Propaedeutics of Internal Medicine
  • Zaporizhzhya, Ukraine, 69600
    • Municipal Institution "Zaporizhzhska Regional Clinical Hospital" of Zaporizhzha Regional Council, gastroenterology department
• United Kingdom
  • Harrow, United Kingdom, HA1 3UJ
    • London North West University Healthcare NHS Trust (LNWH), St Mark's Hospital, R&D Department, Northwick Park Hospital
  • London, United Kingdom, NW1 2PG
    • University College London Hospitals NHS Foundation Trust
  • London, United Kingdom, E1 1BB
    • Barts Health NHS Trust, of Royal London Hospital
  • Prescot, United Kingdom, L35 5DR
    • St Helens & Knowsley Teaching Hospitals NHS Trust, Whiston Hospital
  • Shrewsbury, United Kingdom, CV2 2DX
    • University Hospitals Coventry and Warwickshire NHS Trust, University Hospital
  • Shrewsbury, United Kingdom, SY3 8XQ
    • Shrewsbury and Telford Hospitals NHS Trust, Royal Shrewsbury Hospital
  • Wolverhampton, United Kingdom, WV10 0QP
    • The Royal Wolverhampton NHS Trust, New Cross Hospital
• United States
  • Arizona
    • Tucson, Arizona, United States, 85710
      • Del Sol Research Management, LLC
  • California
    • Los Angeles, California, United States, 90036
      • Axis Clinical Trials
    • Ventura, California, United States, 93003
      • Ventura Clinical Trials
  • Florida
    • Lighthouse Point, Florida, United States, 33071
      • Alliance Medical Research, LLC
    • Medley, Florida, United States, 33166
      • Medley Research Associates
    • Miami, Florida, United States, 33155-4630
      • Global Life Research LLC
    • Pembroke Pines, Florida, United States, 33026-3240
      • Family Clinical Trials
    • Tampa, Florida, United States, 33607
      • Clinical Research Trials of Florida, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Atlanta Gastroenterology Associates, Llc
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, P.C.
  • Massachusetts
    • Brockton, Massachusetts, United States, 02302
      • Commonwealth Clinical Studies
  • North Carolina
    • Salisbury, North Carolina, United States, 28144
      • PMG Research of Salisbury, LLC
  • South Carolina
    • Charleston, South Carolina, United States, 29406-7132
      • Clinical Trials of South Carolina
  • Texas
    • Bellaire, Texas, United States, 77401
      • First Street Surgical Hospital
  • Washington
    • Tacoma, Washington, United States, 98405
      • Digestive Health Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

   1. 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
   2. 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 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)

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, 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

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.

8. 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
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/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

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

   • 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
8. Treatment for intestinal pathogens other than C. difficile within 30 days prior to first randomization

9. 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

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 (eGFR) ≤60 mL/min/1.73m²
14. Serum uric acid levels at Screening >1.2 x ULN (for women >6.8 mg/dL, for 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:

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

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

    1. Use of intravenous corticosteroids
    2. Use of thiopurines including azathioprine, mercaptopurine and 6-thioguanine
    3. Use of 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:

    1. anti-tumor necrosis factor α antibodies (infliximab, adalimumab, golimumab, including their biosimilars) within 4 weeks before first randomization
    2. 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:

    • 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

28. 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
29. Known hypersensitivity to DHODH inhibitors (teriflunomide, leflunomide) or any ingredient of the investigational product
30. Pregnancy or breastfeeding
31. History of drug or alcohol abuse during the past year
32. Concurrent participation in any other clinical trial using an investigational medicinal product or medical device
33. An employee of an investigator or sponsor or an immediate relative of an investigator

Exclusion criteria for open-label treatment extension arm

1. 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 *
2. 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

3. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 10 mg IMU-838 (Induction); 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; IMU-838 tablet; Other Names: vidofludimus calcium; IM90838
Experimental: 30 mg IMU-838 (Induction); 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; IMU-838 tablet; Other Names: vidofludimus calcium; IM90838
Experimental: 45 mg IMU-838 (Induction); 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; IMU-838 tablet; Other Names: vidofludimus calcium; IM90838
Experimental: 10 mg IMU-838 (Maintenance); Two 5 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse.	Drug: IMU-838; IMU-838 tablet; Other Names: vidofludimus calcium; IM90838
Experimental: 30 mg IMU-838 (Maintenance); Two 15 mg tablets once daily of IMU-838 until Week 50 or ulcerative colitis relapse.	Drug: IMU-838; IMU-838 tablet; Other Names: vidofludimus calcium; IM90838
Experimental: 30 mg IMU-838 (Open-label); 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; IMU-838 tablet; Other Names: vidofludimus calcium; IM90838
Placebo Comparator: placebo (Induction); The placebo tablets will be identical to the IMU-838 tablets in terms of appearance, constitution of inactive ingredients, and packaging.	Drug: Placebo; Tablets manufactured to mimic IMU-838 tablets; Other Names: Placebo (for IMU-838)
Placebo Comparator: placebo (Maintenance); 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; Tablets manufactured to mimic IMU-838 tablets; Other Names: Placebo (for IMU-838)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Induction Phase: Symptomatic Remission and Endoscopic Healing at Week 10	Composite endpoint: Proportion of patients with both, symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) and endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10. All patients who were randomized to 30 mg/day and 45 mg/day were used for the assessment of the primary efficacy endpoint	10 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Induction Phase: Symptomatic Remission and Endoscopic Healing at Different Doses at Week 10	Proportion of patients with both symptomatic remission and endoscopic healing at Week 10 (all individual IMU-838 doses were compared with one another and to placebo)	10 weeks
Induction Phase: Symptomatic Remission	Proportion of patients achieving symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) during the induction phase	22 weeks
Induction Phase: Time to Achieving Symptomatic Remission	Time to achieving symptomatic remission (Mayo rectal bleeding subscore = 0 and Mayo stool frequency subscore of 0 or 1) within the extended induction phase	22 weeks
Induction Phase: Proportion of Patients With Clinical Response	Proportion of patients with clinical response (decrease from Baseline in the full Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1) at Week 10	10 weeks
Induction Phase: Proportion of Patients With Endoscopic Healing	Proportion of patients with endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 10	10 weeks
Induction Phase: Proportion of Patients With Symptomatic Response	Proportion of patients with symptomatic response (≥1-point decrease from Baseline in Mayo PRO-2 score) during the induction phase (including extended induction phase)	22 weeks
Induction Phase: Full Mayo Score	Change in full Mayo Score from Baseline to Week 10. The full Mayo score is composed of 4 categories (bleeding, stool frequency, physician assessment, and endoscopic appearance) each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 12. A higher score indicates a worse outcome.	10 weeks
Induction Phase: Partial Mayo Score	Change in partial mayo score over 10 or 22 weeks. The partial Mayo score includes only the non-invasive Mayo subscores, ie, stool frequency, rectal bleeding, and physician's global assessment (each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 9). A higher score indicates a worse outcome.	22 weeks
Induction Phase: Patient Reported Outcome (PRO)-2 Mayo Score	Change in PRO-2 Mayo score over 10 or 22 weeks. Mayo PRO-2 score, ie, stool frequency and rectal bleeding score each rated from 0 to 3 that are added up to give a total score that ranges from 0 to 6. A higher score indicates a worse outcome.	22 weeks
Induction Phase: Fecal Calprotectin (fCP)	Time course of biomarker fCP in stool samples during extended induction phase	22 weeks
Induction Phase: C-reactive Protein (CRP)	Time course of biomarker CRP in blood samples during extended induction phase	22 weeks
Safety: Adverse Events	Incidence and Severity of AEs during the induction and maintenance phases	50 weeks
Safety: Number of Participants With Clinically Significant Findings During Physical Examination	The emergence of any clinically significant findings compared to screening captured during the induction and maintenance phases	50 weeks
Safety: Body Weight	Changes in body weight during the induction and maintenance phases	50 weeks
Safety: Blood Pressure	Changes in blood pressure (mm Hg) during the induction and maintenance phases	50 weeks
Safety: Heart Rate	Changes in heart rate (beats per minute) during the induction and maintenance phases	50 weeks
Safety: 12-lead Electrocardiogram (ECG)	Number of patients with clinically significant changes in ECG	50 weeks
Safety: Hematology	Number of participants with abnormal hematology laboratory values (treatment-emergent adverse events [TEAEs] related to hematological abnormalities)	up to Week 50
Safety: Blood Chemistry	Number of participants with abnormal blood chemistry laboratory values (TEAES related to clinical chemistry abnormalities)	50 weeks
Safety: Coagulation	Number of participants with clinically significant abnormal coagulation laboratory values	10 weeks
Safety: Urinalysis	Number of participants with abnormal urinalysis laboratory values (TEAEs related to urinalysis)	50 weeks
Safety: Micro Ribonucleic Acid-122 Expression	Micro ribonucleic acid-122 (miR-122) expression (before first dose and 24 hours after first dose - foldchange of normalized expression values )	24 hours
Pharmacodynamics (PK): IMU-838 Trough Level	Measurement of pre-dose (trough) blood plasma levels of IMU-838 throughout the induction period	Day 0, Day 1, Day 7, Week 2 and Week 10
PK: IMU-838 Plasma Level	Measurement of post-dose blood plasma levels of IMU-838 at Week 2	2 weeks
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 in Symptomatic Remission	Proportion of patients in symptomatic remission (Mayo rectal bleeding subscore = 0, and Mayo stool frequency subscore of 0 or 1) by visit up to Week 50 in maintenance phase	Week 14, Week 30, Week 50
Maintenance Phase: Mayo PRO-2 Score	Time course of Mayo PRO-2 score until Week 50. Mayo patient-reported outcome score, ie, stool frequency and rectal bleeding score each rated from 0 to 3 3 that are added up to give a total score that ranges from 0 to 6. A higher score indicates a worse outcome.	50 weeks
Maintenance Phase: Time to Relapse	Time to symptomatic ulcerative colitis (UC) relapse	50 weeks
Maintenance Phase: Proportion of Patients Without Relapse	Proportion of patients without symptomatic UC relapse until Week 50	50 weeks
Maintenance Phase: fCP	Timecourse of biomarker fCP in stool samples	50 weeks
Maintenance Phase: CRP	Timecourse of biomarker CRP in blood samples	50 weeks
Maintenance Phase: Proportion of Patients With Endoscopic Healing	Proportion of patients with endoscopic healing (Modified Mayo endoscopy subscore of 0 or 1) at Week 50 of maintenance phase	50 weeks
Maintenance Phase: Proportion of Patients With Microscopic Healing	Proportion of patients with microscopic healing (Geboes score of =< 3.1) at Week 50 of maintenance phase	50 weeks
Maintenance Phase: Corticosteroid-free Remission	Corticosteroid-free clinical remission (clinical remission and no receipt of systemic or local corticosteroids) at Week 50 in patients receiving corticosteroids at Baseline	50 weeks
Open-label Phase: Symptom Control	Proportion of patients with symptom control	up to 4 years
Open-label Phase: fCP	Timecourse of biomarker fCP in stool samples. Visits were scheduled every 4 weeks (+/-7 days) until 50 weeks of total study participation (ie induction + extended induction, if applicable, maintenance + open-label part) and every 10 weeks (+/-7 days) thereafter. The visit schedule in the OLE after 50 weeks of overall study treatment was changed from a 10-week schedule to a 24 week (+/-14 days) schedule after Protocol Version 6.0 came into force. Because the study was terminated early, EoT varied between patients depending on when patients entered the study and the time a patient participated in the induction and maintenance phases before switching to the OLE.	Baseline, Week 4 OLE, Week 8 OLE, EoT up to 4 years (variable)
Open-label Phase: CRP	Timecourse of biomarker CRP in blood samples. Visits were scheduled every 4 weeks (+/-7 days) until 50 weeks of total study participation (ie induction + extended induction, if applicable, maintenance + open-label part) and every 10 weeks (+/-7 days) thereafter. The visit schedule in the OLE after 50 weeks of overall study treatment was changed from a 10-week schedule to a 24 week (+/-14 days) schedule after Protocol Version 6.0 came into force. Because the study was terminated early, EoT varied between patients depending on when patients entered the study and the time a patient participated in the induction and maintenance phases before switching to the OLE.	Baseline, Week 4 OLE, Week 8 OLE, Week 10 OLE, Week 12 OLE, Week 16 OLE, Week 20 OLE, Week 24 OLE, Week 28 OLE, Week 32 or 38 OLE (depending if entry was after extended induction phase), EoT up to 4 years (variable)

Collaborators and Investigators

• Sponsor: Immunic AG
• Investigators: Study Director: Andreas Muehler, Immunic Therapeutics

Publications and helpful links

Helpful Links

• US Food and Drug Administration (FDA). Ulcerative Colitis: Clinical Trial Endpoints. Guidance for Industry.[Online]. 2016.
• European Union (EU). Directive 95/46/EC of the European Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the processing of personal data and on the free movement of such data. [Online].
• EU. Regulation 2016/679 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data, and repealing Directive 95/46/EC (General Data Protection Regulation). 2016; [Online].
• European Medicines Agency (EMA). Guideline on the development of new medicinal products for the treatment of Ulcerative Colitis.[Online]. 2016.
• American Urological Association. Guideline: Diagnosis, evaluation and follow up of asymptomatic mircrohematuria. (AMH) in adults.[Online]. 2012.

Study record dates

Study Major Dates

• Study Start (Actual): March 15, 2018
• Primary Completion (Actual): November 16, 2022
• Study Completion (Actual): November 16, 2022

Study Registration Dates

• First Submitted: November 8, 2017
• First Submitted That Met QC Criteria: November 9, 2017
• First Posted (Actual): November 14, 2017

Study Record Updates

• Last Update Posted (Estimated): March 5, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Ulcerative Colitis; IMU-838; vidofludimus calcium
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Calcium-Regulating Hormones and Agents; Calcium
• Other Study ID Numbers: P2-IMU-838-UC (Other Identifier: Sponsor protocol ID); 2017-003703-22 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No