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About
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).
Full 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.
Enrollment
Sex
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Inclusion criteria
Induction phase
Male and female patients, aged 18 - 80 years
UC diagnosed more than 3 months before Screening (Day-30) as documented in the medical chart
Previous treatment failure defined as:
Active disease defined as
a. Mayo stool frequency score of ≥2 at Screening Visit 1 b. Mayo rectal bleeding score of ≥1 at Screening Visit 1 c. modified Mayo endoscopy subscore of ≥2 at the screening flexible sigmoidoscopy (endoscopy assessed by an independent central reader blinded to screening center and patient information)
Endoscopic appearance typical for UC and extending >15 cm from the anal verge as confirmed by an independent central reader (blinded to screening center and patient information)
Laboratory values: Neutrophil count >1500 cells/µL, platelet count ≥100 000 /mm3, serum creatinine <1.5 x upper limit of normal (ULN), total bilirubin, alanine aminotransferase (ALT), and gamma-glutamyl transferase (GGT) <1.5 x ULN
Female patients must:
a. Be of non-child-bearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening) or post-menopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
b. If of child-bearing potential, must have a negative pregnancy test at Screening (blood test) and before the first study drug administration (Day 0 urine test). They must agree not to attempt to become pregnant, must not donate ova, and must use a highly effective contraceptive method 2 months before Screening, during treatment with IMU-838, and at least 3 months after the last dose of study therapy
Highly effective forms of birth control are those with a failure rate less than 1% per year and include:
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:
And additionally, for Poland only:
Ability to understand and comply with study procedures and restrictions
The patient is legally competent, has been informed of the nature, the scope and the relevance of the study, voluntarily agrees to participation and the study's provisions and has duly signed the informed consent form
Maintenance phase
Open-label treatment extension arm
OR
Patient is in the extended induction phase, had completed all Week 10 assessments, and has not reached symptomatic remission during or at the end of the extended induction phase, Or Patient is in the maintenance phase and discontinues from the maintenance phase due to symptomatic UC relapse or other reasons with a flexible sigmoidoscopy performed at discontinuation (if the previous sigmoidoscopy had been performed more than 4 weeks before discontinuation)
OR
Patient has completed the maintenance phase as scheduled (including all Week 50 assessments)
Exclusion criteria
Gastrointestinal exclusion criteria
Diagnosis of Crohn's disease, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis
Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
History of colectomy with ileorectal anastomosis or ileal-pouch anal anastomosis or imminent need for colectomy (i.e. colectomy is being planned)
Active therapeutically uncontrollable abscess or toxic megacolon
Malabsorption or short bowel syndrome
History of colorectal cancer or colorectal dysplasia (with the exception of dysplasia in polyps which have been removed)
Infectious disease exclusion criteria
Clostridium difficile (C. difficile) infection
Treatment for intestinal pathogens other than C. difficile within 30 days prior to first randomization
Other chronic systemic infections
Any live vaccinations within 30 days prior to study drug administration except for the influenza vaccine
Other medical history and concomitant disease exclusion criteria
Known history of nephrolithiasis or underlying condition with a strong association of nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia
Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial
Renal impairment i.e. estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m²
Serum uric acid levels at Screening >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL)
History or clinical diagnosis of gout
Known or suspected Gilbert syndrome
Indirect (unconjugated) bilirubin ≥1.2 x ULN at Screening (i.e. ≥ 1.1 mg/dL)
Concurrent malignancy or prior malignancy within the previous 10 years except for the following: adequately-treated non-melanoma skin cancer and adequately-treated cervical cancer
Therapy exclusion criteria
Use of any investigational product within 8 weeks or 5 x the respective half-life before first randomization, whatever is longer
Use of the following medications within 2 weeks before first randomization:
Use of the following medications within 4 weeks before first randomization:
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:
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:
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
Primary purpose
Allocation
Interventional model
Masking
263 participants in 8 patient groups, including a placebo group
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Data sourced from clinicaltrials.gov
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