Phase 2 Dose-finding IMU-838 for Ulcerative Colitis

  • STATUS
    Recruiting
  • End date
    Jun 30, 2029
  • participants needed
    240
  • sponsor
    Immunic AG
Updated on 8 July 2021
Investigator
Andreas Muehler
Primary Contact
Hospital da Senhora da Oliveira - Guimar es, EPE (9.4 mi away) Contact
+190 other location
corticosteroids
remission
methotrexate
endoscopy
adalimumab
infliximab
flexible sigmoidoscopy
tumor necrosis factor
mercaptopurine
vedolizumab
azathioprine
biosimilar
tumor necrosis factor alpha
golimumab
tumour necrosis
immunomodulators
hematochezia

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 (IFN), 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.

Details
Condition Ulcerative Colitis, Ulcerative Colitis (Pediatric)
Treatment Placebo, IMU-838
Clinical Study IdentifierNCT03341962
SponsorImmunic AG
Last Modified on8 July 2021

Eligibility

Yes No Not Sure

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 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
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/L, 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
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
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
Symptomatic remission achieved at Week 10 or Week 22 of the induction phase
Open-label treatment extension arm
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
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 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
\. 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/1.73m
\. 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 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
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