Phase 2 Dose-finding IMU-838 for Ulcerative Colitis

Ulcerative Colitis Clinical Trial

— CALDOSE-1  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03341962
• Other study ID #: P2-IMU-838-UC
• Secondary ID: P2-IMU-838-UC201
• Status: Terminated
• Phase: Phase 2
• Start date: March 15, 2018
• Est. completion date: November 16, 2022

Study information

• Verified date: February 2024
• Source: Immunic AG
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 263
• Est. completion date: November 16, 2022
• Est. primary completion date: November 16, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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 a 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 a 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.

Related Conditions & MeSH terms

• Colitis
• Colitis, Ulcerative
• Ulcer
• Ulcerative Colitis

Intervention

Drug:
• IMU-838
IMU-838 tablet
• Placebo
Tablets manufactured to mimic IMU-838 tablets

Locations

Country	Name	City	State
Albania	Durres Regional Hospital	Durres
Albania	Regional Hospital of Shkoder	Shkoder
Albania	University Hospital Center Mother Teresa	Tirana
Belarus	Gomel Regional Clinical Hospital	Gomel
Belarus	Republican Scientific and Practical Center for Radiation Medicine and Human Ecology	Gomel
Belarus	Vitiebsk State Order of Peoples' Friendship Medical University	Vitebsk
Bosnia and Herzegovina	University Clinical Centre of the Republic of Srpska, Internal Medicine Clinic, Department of Gastroenterology and Hepatology	Banja Luka
Bosnia and Herzegovina	University Clinical Hospital Mostar, Internal Medicine Clinic, Department of Gastroenterology	Mostar
Bulgaria	Multiprofile Hospital for Active Treatment Blagoevgrad AD	Blagoevgrad
Bulgaria	Mhat Byala	Byala
Bulgaria	Multiprofile Hospital for Active Treatment "Dr. Hristo Stambolski" EOOD	Kazanlak
Bulgaria	Medical Center "Medconsult Pleven" OOD	Pleven
Bulgaria	Medical Center Exacta Medica	Pleven
Bulgaria	University Multiprofile Hospital for Active Treatment "Sveti Georgi" EAD, Plovdiv, Gastroenterology clinic	Plovdiv
Bulgaria	Diagnostic-Consulting Center "Convex" EOOD	Sofia
Bulgaria	Medical Center "Hera" EOOD	Sofia
Croatia	General Hospital Bjelovar	Bjelovar
Croatia	Clinical Hospital Center Osijek	Osijek
Croatia	Clinical Hospital Center Rijeka	Rijeka
Croatia	Clinical Hospital Center Split	Split
Croatia	General Hospital Vukovar	Vukovar
Croatia	Clinical Hospital Center Split	Zagreb
Croatia	Clinical Hospital Center Zagreb	Zagreb
Croatia	Clinical Hospital Dubrava	Zagreb
Croatia	Polyclinic Solmed Zagreb	Zagreb
Czechia	Asclepiades - Interna a gastroenterologie s.r.o. - Havírov	Havírov
Czechia	Hepato-Gastroenterologie HK, s.r.o. Poliklinika III	Hradec Králové
Czechia	Artroscan s.r.o.	Ostrava - Trebovice
Czechia	FaraCol s.r.o. - Prague	Praha
Czechia	Klinika ResTrial	Praha
Czechia	MEDICON a.s. - Poliklinika Budejovická Gastroenterologie	Praha
Czechia	Všeobecná fakultní nemocnice v Praze IV. interní klinika VFN a 1. LF UK	Praha
Georgia	Academician Z.Tskhakaia West Georgia National Center of Interventional Medicine	Kutaisi
Georgia	LTD Unimedi Kakheti - Caraps Medline	Tbilisi
Netherlands	Amsterdam UMC, locatie AMC	Amsterdam
Netherlands	Albert Schweitzer Hospital	Dordrecht
Netherlands	Elisabeth-TweeSteden Hospital	Tilburg
North Macedonia	City General Hospita 8th September	Skopje
North Macedonia	University Clinic for Hematology - Skopje - Macedonian Hematology Association	Skopje
Poland	Centrum Uslug Medycznych MaxMed	Bochnia
Poland	Centrum Medyczne Pratia Gdynia	Gdynia
Poland	Centrum Medyczne Endo-med Sp. z o.o.	Karczew
Poland	Vita Longa Sp. z o.o.	Katowice
Poland	GLOBE Badania Kliniczne Sp. z o.o.	Klodzko
Poland	Centrum Medyczne Med-Gastr Sp. z o.o. Spólka Komandytowa	Lódz
Poland	Salve Medica Sp. z o.o. Spólka Komandytowa	Lódz
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie Oddzial Gastroenterologii	Lublin
Poland	Zaklad leczniczy ALLMEDICA BADANIA KLINICZNE Sp. z o.o. Sp. K.	Nowy Targ
Poland	Etyka Osrodek Badan Klinicznych	Olsztyn
Poland	Ars Medical - Szpital, Ars Medical - Ambulatorium	Pila
Poland	Niepubliczny Zaklad Opieki Zdrowotnej Centrum Medyczne HCP - Lecznictwo Stacjonarne	Poznan
Poland	SOLUMED Centrum Medyczne	Poznan
Poland	Endoskopia Sp. z o.o.	Sopot
Poland	Centrum Badawcze Wspólczesnej Terapii, Prywatny Gabinet Lekarski dr Anna Bochenek-Mularczyk	Warszawa
Poland	Klinika Medifem	Warszawa
Poland	Centrum Medyczne OMNI Clinic Sp. z o.o. Spólka Komandytowa	Wroclaw
Poland	Przychodnia Vistamed	Wroclaw
Portugal	Centro Hospitalar e Universitário de Coimbra, EPE - Hospitais da Universidade de Coimbra	Coimbra
Portugal	Hospital da Senhora da Oliveira - Guimarães, EPE	Guimarães
Portugal	Centro Hospitalar de Entre o Douro e Vouga, EPE - Hospital São Sebastião	Santa Maria da Feira
Romania	Institutul Clinic Fundeni, Sectia Clinica Gastroenterologie III	Bucharest
Romania	S.C. MEDLIFE S.A., Sectia Gastroenterologie	Bucharest
Romania	Spitalul Clinic Colentina, Sectia Gastroenterologie	Bucharest
Romania	S.C. Cabinet Particular Policlinic Algomed SRL, Specialitatea Gastroenterologie	Timisoara
Russian Federation	Kazan State Medical University	Kazan
Russian Federation	SEI HPE "Kuban State Medical University" of MoH and SD, CBHS Regional Clinical Hospital No.2	Krasnodar
Russian Federation	Central Clinical Hospital of the Russian Academy of Sciences	Moscow
Russian Federation	Clinical Research Institution of Moscow Region named after M. F. Vladimirsky	Moscow
Russian Federation	Federal Medical Biophysical Center n.a. Burnazyan	Moscow
Russian Federation	Novosibirskiy Gastrocenter, LLC	Novosibirsk
Russian Federation	FSBEI HE "Military Medical Academy n.a. S.M. Kirov" under the Ministry of Defence of Russian Federation	Saint Petersburg
Russian Federation	Gastroenterological Center "Expert" LLC	Saint Petersburg
Russian Federation	Hospital of Saint Martyr Elizaveta	Saint Petersburg
Russian Federation	Research Center Eco-Safety, LLC	Saint Petersburg
Russian Federation	Saint Petersburg State Medical University named after I.P. Pavlov	Saint Petersburg
Russian Federation	City Hospital No. 5 - Sochi	Sochi
Russian Federation	Regional State Autonomous Healthcare Institution "Tomsk Regional Clinical Hospital"	Tomsk
Russian Federation	Siberian State Medical University	Tomsk
Serbia	Clinic for gastroenterohepatology	Belgrade
Serbia	Clinical Hospital Center Zemun	Belgrade
Serbia	University Hospital Center Bezaniska Kosa	Belgrade
Serbia	Clinical Center Kragujevac	Kragujevac
Serbia	General Hospital Leskovac	Leskovac
Serbia	Clinical Center Nis	Nis
Serbia	General Hospital Djordje Joanovic, Internal Deases Department, Gastroenterology	Zrenjanin
Spain	Hospital Juan Ramón Jimenez	Huelva
Turkey	Bezmiâlem Vakif Üniversitesi	Fatih
Turkey	Istanbul Universitesi Istanbul Tip Fakultesi Gastroenteroloji Bilim Dali	Fatih
Turkey	Karadeniz Teknik Üniversitesi Tip Fakultesi	Trabzon
Ukraine	Public Enterprise "Dnipropetrovsk regional clinical hospital named after I.I. Mechnikova", Department of Gastroenterology (Hepatology)	Dnipro
Ukraine	Ivano-Frankivsk City Clinical Hospital No. 1	Ivano-Frankivs'k
Ukraine	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	Municipal Non-profit Enterprise "City Clinical Hospital #2 named after prof. O.O. Shalimova", of Kharkiv City Council, Proctology Department	Kharkiv
Ukraine	Municipal Non-profit Enterprise of Kharkiv Regional Council "Regional Clinical Hospital", Gastroenterology Department	Kharkiv
Ukraine	Private Enterprise Private Manufacturing Firm "Acinus", Treatment and diagnostic Centre	Kropyvnytskyi
Ukraine	Kyiv City Clinical Hospital #1, Therapeutics Department #2	Kyiv
Ukraine	Kyiv City Clinical Hospital #18, Proctology Department, National Medical University named after O.O.Bogomolets, Chair of Surgery #1	Kyiv
Ukraine	Kyiv Regional Clinical Hospital No 2	Kyiv
Ukraine	Medical Center Medical Clinic Blagomed LLC	Kyiv
Ukraine	Medical Centre of Limited Liability Company "Medical Centre "Consilium Medical", clinico-consultation department	Kyiv
Ukraine	Medical Centre of Limited Liability Company "Medical Centre "Dopomoga plus""	Kyiv
Ukraine	Shalimov's National Institute of surgery and transplantation	Kyiv
Ukraine	Volyn Regional Clinical Hospital	Lutsk
Ukraine	Municipal Non-profit Enterprise of Lviv Regional Council "Lviv Regional Clinical Hospital", proctology department, Danylo Galytsky Lviv National Medical University, Chair of Surgery #1	Lviv
Ukraine	KARDIOKOM Ltd.	Mykolaiv
Ukraine	Transcarpathian Regional Clinical Hospital named after Andriy Novaka, gastroenterology department	Uzhhorod
Ukraine	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	Vinnytsia
Ukraine	Municipal Non-profit Enterprise "Vinnytsia Regional Clinical Hospital named after M.I. Pyrogova of Vinnytsia Regional Council, Regional Specialized Clinical Gastroenterological Center,	Vinnytsia
Ukraine	Municipal Institution "Zaporizhzhska Regional Clinical Hospital" of Zaporizhzha Regional Council, gastroenterology department	Zaporizhzhya
United Kingdom	London North West University Healthcare NHS Trust (LNWH), St Mark's Hospital, R&D Department, Northwick Park Hospital	Harrow
United Kingdom	Barts Health NHS Trust, of Royal London Hospital	London
United Kingdom	University College London Hospitals NHS Foundation Trust	London
United Kingdom	St Helens & Knowsley Teaching Hospitals NHS Trust, Whiston Hospital	Prescot
United Kingdom	Shrewsbury and Telford Hospitals NHS Trust, Royal Shrewsbury Hospital	Shrewsbury
United Kingdom	University Hospitals Coventry and Warwickshire NHS Trust, University Hospital	Shrewsbury
United Kingdom	The Royal Wolverhampton NHS Trust, New Cross Hospital	Wolverhampton
United States	McFarland Clinic, P.C.	Ames	Iowa
United States	Atlanta Gastroenterology Associates, LLC	Atlanta	Georgia
United States	First Street Surgical Hospital	Bellaire	Texas
United States	Commonwealth Clinical Studies	Brockton	Massachusetts
United States	Clinical Trials of South Carolina	Charleston	South Carolina
United States	Alliance Medical Research, LLC	Lighthouse Point	Florida
United States	Axis Clinical Trials	Los Angeles	California
United States	Medley Research Associates	Medley	Florida
United States	Global Life Research LLC	Miami	Florida
United States	Family Clinical Trials	Pembroke Pines	Florida
United States	PMG Research of Salisbury, LLC	Salisbury	North Carolina
United States	Digestive Health Specialists	Tacoma	Washington
United States	Clinical Research Trials of Florida, Inc.	Tampa	Florida
United States	Del Sol Research Management, LLC	Tucson	Arizona
United States	Ventura Clinical Trials	Ventura	California

Sponsors (1)

Lead Sponsor	Collaborator
Immunic AG

Countries where clinical trial is conducted

United States,  Albania,  Belarus,  Bosnia and Herzegovina,  Bulgaria,  Croatia,  Czechia,  Georgia,  Netherlands,  North Macedonia,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Spain,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Induction Phase: Fecal Calprotectin (fCP)	Time course of biomarker fCP in stool samples during extended induction phase	22 weeks
Secondary	Induction Phase: C-reactive Protein (CRP)	Time course of biomarker CRP in blood samples during extended induction phase	22 weeks
Secondary	Safety: Adverse Events	Incidence and Severity of AEs during the induction and maintenance phases	50 weeks
Secondary	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
Secondary	Safety: Body Weight	Changes in body weight during the induction and maintenance phases	50 weeks
Secondary	Safety: Blood Pressure	Changes in blood pressure (mm Hg) during the induction and maintenance phases	50 weeks
Secondary	Safety: Heart Rate	Changes in heart rate (beats per minute) during the induction and maintenance phases	50 weeks
Secondary	Safety: 12-lead Electrocardiogram (ECG)	Number of patients with clinically significant changes in ECG	50 weeks
Secondary	Safety: Hematology	Number of participants with abnormal hematology laboratory values (treatment-emergent adverse events [TEAEs] related to hematological abnormalities)	up to Week 50
Secondary	Safety: Blood Chemistry	Number of participants with abnormal blood chemistry laboratory values (TEAES related to clinical chemistry abnormalities)	50 weeks
Secondary	Safety: Coagulation	Number of participants with clinically significant abnormal coagulation laboratory values	10 weeks
Secondary	Safety: Urinalysis	Number of participants with abnormal urinalysis laboratory values (TEAEs related to urinalysis)	50 weeks
Secondary	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
Secondary	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
Secondary	PK: IMU-838 Plasma Level	Measurement of post-dose blood plasma levels of IMU-838 at Week 2	2 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Maintenance Phase: Time to Relapse	Time to symptomatic ulcerative colitis (UC) relapse	50 weeks
Secondary	Maintenance Phase: Proportion of Patients Without Relapse	Proportion of patients without symptomatic UC relapse until Week 50	50 weeks
Secondary	Maintenance Phase: fCP	Timecourse of biomarker fCP in stool samples	50 weeks
Secondary	Maintenance Phase: CRP	Timecourse of biomarker CRP in blood samples	50 weeks
Secondary	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
Secondary	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
Secondary	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
Secondary	Open-label Phase: Symptom Control	Proportion of patients with symptom control	up to 4 years
Secondary	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)
Secondary	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)

External Links

•   American Urological Association. Guideline: Diagnosis, evaluation and follow up of asymptomatic mircrohematuria. (AMH) in adults.[Online]. 2012.
•   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.
•   US Food and Drug Administration (FDA). Ulcerative Colitis: Clinical Trial Endpoints. Guidance for Industry.[Online]. 2016.