A phase 2 Dose-finding study of IMU-838 in patients with active Crohn’s disease

• Register: EUCTR
• Last refreshed on: 8 August 2022
• Main ID: EUCTR2018-001895-39-HR
• Date of registration: 20/01/2020
• Prospective Registration: No
• Primary sponsor: Immunic AG
• Public title: A phase 2 Dose-finding study of IMU-838 in patients with active Crohn’s disease
• Scientific title: A phase 2, multicenter, randomized, double-blind, placebo-controlled, dose-finding trial to evaluate the efficacy and safety of IMU-838 for treatment of patients with active Crohn’s disease with an option for open-label treatment extension (CALDOSE-2) - CALDOSE-2
• Date of first enrolment: 21/11/2019
• Target sample size: 258
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001895-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Bulgaria, Croatia, Czech Republic, Germany, Netherlands, Poland, Romania, Russian Federation, Serbia, Slovenia, Spain, Ukraine, United Kingdom, United States

Contacts

• Name: Global Regulatory Submissions
• Affiliation: Covance Clinical and Periapproval Services Ltd

• Name: Global Regulatory Submissions
• Affiliation: Covance Clinical and Periapproval Services Ltd

Key inclusion & exclusion criteria

Inclusion criteria:
INDUCTION TREATMENT PHASE
1 Male or female patient, aged 18-80 years
2 Confirmed diagnosis of active luminal CD, at least 3 months before Screening Visit S1
3 SES-CD score of at least 6, or of at least 4 in patients with isolated ileitis (screening ileocolonoscopy and SES-CD score assessed by an in-dependent central reader blinded to center and patient information)
4 At least one aphthous ulcerative lesion or more severe ulcer accessible by ileocolonoscopy (as confirmed by an independent central blinded reader from screening ileocolonoscopy)
5 Full CDAI score =220 and =450 at Screening Visit S1
6 Average daily very soft or liquid stool frequency score (based on the BSFS) =4.0 and/or AP-CDAI score =2.0 at Screening Visit S1 (according to retrospective data of the preceding 7 days)
7 Previous treatment failure defined as:
a Patient had an inadequate response with, lost response to, or was in-tolerant to approved or experimental immunomodulators or biologics. A maximum of 3 treatment failures with biologic drugs i.e. anti-tumor necrosis factor alpha antibodies, certolizumab pegol, vedolizumab, natalizumab, ustekinumab, or experimental antibodies, i.e. not approved for the use in CD or not approved but in development for CD, is allowed; or
b Patient had an inadequate response to corticosteroids (a corticosteroidrefractory patient is defined as having active disease despite prednisolone up to 1 mg/kg/day for a period of 4 weeks), was intolerant to corticosteroids, or is corticosteroid dependent (a corticosteroid-dependent patient is defined as i) unable to reduce steroids below the equivalent of prednisolone 10 mg/day [or budesonide be-low 3 mg/day] within 3 months of starting steroids, without recurrent active disease, or ii) who has a relapse within 3 months of stopping steroids.
8 Laboratory values: Neutrophil count >1500 cells/µL (>1.5 x 10^9 cells/L), platelet count
=100 000/mm3 (=100 x 10^9/L), serum creatinine <1.5 upper limit of normal (ULN), total bilirubin, alanine aminotransferase, and aspartate aminotransferase <1.5 ULN
9 Female patients
- must be of non-childbearing potential i.e. surgically sterilized (hysterectomy, bilateral salpingectomy, bilateral oophorectomy at least 6 weeks before Screening Visit S1) or postmenopausal (where postmenopausal is defined as no menses for 12 months without an alternative medical cause), or
- if of childbearing potential, must have a negative pregnancy test at Screening Visit S1 (blood test) and at Day 0 before IMP administration (urine test). They must agree not to attempt to become pregnant, not to donate ova and to use a highly effective contraceptive method at the start of the trial (trial consent), during treatment with IMU 838, and for at least 30 days after the last intake of the IMP.
10 Male patients must agree not to father a child or to donate sperm starting at Screening Visit S1, throughout the clinical trial and for 30 days after the last intake of the IMP. Male patients must also
- 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 the IMP and for at least 30 days after the last intake of the IMP, and
- if they have a female partner of childbearing potential, ensure that the partner uses a highly effective contraceptive method as outlined in inclusion criterion 9
- if they have a pregnant partner, use condoms while taking the I
Exclusion criteria:
GI CRITERIA
1 Diagnosis of ulcerative colitis, inflammatory bowel disease type unclassified, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis
2 High likelihood of requiring bowel surgery during the 38 weeks of the BT period
3 Ileostomy, colostomy, or known fixed symptomatic stenosis of the intestine
4 Ileorectal anastomosis or ileal-pouch anal anastomosis
5 Celiac disease
6 Presence of intra-abdominal or perianal abscess that is undrained
7 History of subtotal colectomy or imminent need for colectomy (i.e. colectomy is being planned)
8 Malabsorption or short-bowel syndrome
9 History of small bowel or colorectal cancer or gastrointestinal dysplasia (with the exception of dysplasia in polyps that have been removed)

INFECTIOUS DISEASE
10 Clostridium difficile (C. difficile) infection
a Evidence of, or treatment for, C. difficile infection within 30 days before randomization
b Positive C. difficile toxin B stool assay at Screening Visit S1
11 Treatment for intestinal pathogens other than C. difficile within 30 days before randomization
12 Other chronic systemic infections
a History of chronic systemic infections including but not limited to tuberculosis, HIV, HBV, or HCV, within 6 months before Screening Visit S1
b Positive interferon-gamma release assay for Mycobacterium tuberculosis at Screening Visit S1
c Positive HBV surface antigen (HBsAg), hepatitis B core antibody (HBcAb), positive HCV and/or HIV-antigen-antibody (HIV-Ag/Ab) test at Screening Visit S1 (even without detectable virus load in blood)
13 Any live vaccinations within 30 days before randomization except for the influenza vaccine

OTHER MEDICAL HISTORY AND CONCOMITANT DISEASE EXCLUSION CRITERIA
14 Known history of nephrolithiasis or underlying condition with a strong association o nephrolithiasis, including hereditary hyperoxaluria or hereditary hyperuricemia
15 Diagnosis or suspected liver function impairment which may cause, as assessed by the investigator, a potential for fluctuating liver function tests during this trial
16 Renal impairment i.e. eGFR >60 mL/min/1.73 m²
17 Serum uric acid levels at Screening Visit S1 >1.2 x ULN (for women >6.8 mg/dL, for men >8.4 mg/dL)
18 History or clinical diagnosis of gout
19 Known or suspected Gilbert syndrome
20 Indirect (unconjugated) bilirubin =1.2 x ULN (i.e. =1.1 mg/dL) at Screening Visit S1
21 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
22 Use of any IMP within 8 weeks or 5 x the respective half-life before randomization, whichever is longer
23 Use of the following medications within 2 weeks before randomization:
a Tofacitinib
b Methotrexate,
c Mycophenolate mofetil
d Any calcineurin inhibitors (e.g. tacrolimus, cyclosporine, or pimecrolimus)
e Oral systemic corticosteroids >20 mg/day prednisolone equivalent including beclomethasone dipropionate (at >5 mg/day) and budesonide (at >9 mg/day)
f Oral aminosalicylates (e.g. mesalazines) >4 g/day
24 Use of the following medications within 4 weeks before randomization:
a Use of intravenous corticosteroids
b Use of thiopurines including azathioprine, 6-mercaptopurine and 6-thioguanine
c Use of any rectal or topical aminosalicylates and/or budesonide
25 Use of oral systemic corticosteroids =20 mg/day prednisolone equivalent including beclomethasone dipropionate (a

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Crohn’s disease (CD)
MedDRA version: 20.0 Level: PT Classification code 10011401 Term: Crohn's disease System Organ Class: 10017947 - Gastrointestinal disorders

Therapeutic area: Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]

Intervention(s)

Product Name: vidofludimus calcium
Product Code: IMU-838
Pharmaceutical Form: Tablet
INN or Proposed INN: Vidofludimus calcium
Current Sponsor code: IMU-838
Other descriptive name: IM90838
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: vidofludimus calcium
Product Code: IMU-838
Pharmaceutical Form: Tablet
INN or Proposed INN: Vidofludimus calcium
Current Sponsor code: IMU-838
Other descriptive name: IM90838
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 22.5-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Induction treatment phase (BT period)
• Proportion of patients with symptomatic remission at Week 14 i.e. fulfilling the following criteria:
- Remission in AP-CDAI, defined as AP-CDAI score =1 and not worse than at Baseline,
and
- Remission in SF-CDAI, defined as SF-CDAI score =2.8 and not worse than at Baseline
For the primary analysis, the 45 mg/day IMU-838 will be compared to placebo.

Main Objective: To determine the optimal dose of IMU-838 to induce symptomatic remission (based on stool frequency [SF] and abdominal pain [AP], as assessed in the Crohn’s Disease Activity Index [CDAI] patient-reported outcome [PRO]-2) in patients with active Crohn’s disease (CD)

Secondary Objective: To determine the optimal dose of IMU-838 to induce endoscopic improvement in patients with active CD.
Further secondary and exploratory objectives
• To evaluate the potential of IMU-838 to induce clinical response and clinical remission
• To evaluate the time course of IMU-838 activity
• To evaluate the durability of response and remission
• To explore the potential of IMU-838 to maintain remission as well as avoid CD relapse
• To evaluate the safety and tolerability of IMU-838 in patients with active CD
• To evaluate trough levels of IMU-838 in patients with active CD
• To assess disease activity markers and biomarkers

Timepoint(s) of evaluation of this end point: AP-CDAI and SF-CDAI: screening, pre-dose and week 14

Secondary Outcome(s)

Secondary end point(s): Induction treatment phase (BT period)
• Proportion of patients achieving endoscopic improvement at Week 14:
- Reduction of the SES-CD by =50% versus Baseline, or SES-CD score =4 (or in patients with isolated ileitis an SES-CD score =2), a reduction of =2 points from Baseline, and no ulcer sub-score >1 in any of the 5 segments (ileum, right/transverse/left colon, and rectum)
BT period
• Proportion of patients with endoscopic remission at Weeks 14 and 38
• Change in AP-LPS score and SF-CDAI score from Baseline
Proportion of patients with the primary and the key secondary endpoints for the following comparisons:
- 30 mg/day IMU-838 versus placebo
- 30 mg/day versus 45 mg/day IMU-838
• Proportion of patients in clinical remission (full CDAI) at Weeks 14 and 38

Timepoint(s) of evaluation of this end point: Induction treatment phase (BT period)
• Proportion of patients achieving endoscopic improvement,
SES-CD: baseline, w14
BT period
• Proportion of patients with endoscopic remission: w14, w38
• AP-LPS score and SF-CDAI score: screening, pre-dose, w1, w2, w6, w10, w14 and w38
• Proportion of patients in clinical remission (full CDAI): screening, pre-dose, w14 and w38

Secondary ID(s)

2018-001895-39-CZ

P2-IMU-838-CD

Source(s) of Monetary Support

Immunic AG

Ethics review

Status: Approved
Approval date: 03/10/2019
Contact: