Primary 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…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy
Induction treatment phase (BT period)
• Proportion of patients with symptomatic remission at Week 14 i.e. fulfilling
the following criteria:
o Remission in AP-CDAI, defined as AP-CDAI score <=1 and not worse than at
Baseline,
and
o 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
Secondary outcome
Efficacy
Induction treatment phase (BT period)
• Proportion of patients achieving endoscopic improvement at Week 14:
o 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)
For the analysis of the key secondary endpoint, the 45 mg/day IMU-838
dose will be compared to placebo.
The primary endpoint and the key secondary endpoint will be tested
hierarchically. If a statistically significant difference between the treatment
groups is found for the primary endpoint, the analysis of the key secondary
endpoint will be considered confirmative. Otherwise the analysis of the key
secondary endpoint is considered exploratory.
Background summary
Crohn*s disease (CD) is a chronic relapsing, remitting inflammatory
disease of the gastrointestinal tract, the cause of which remains unknown. The
disease affects the gastrointestinal tract discontinuously from mouth to anus,
but most commonly the disease is located both in ileum and colon (40%),
followed by a disease in the small bowel only (30%), and in the colon only
(25%). This disorder leads to severe disability and a significant reduction in
quality of life.
CD is characterized by uncontrolled mucosal inflammation as a result of
a dysregulated immune system involving an excessive T helper 1 (Th1) response.
Activated Th1 cells produce classical pro-inflammatory cytokines such as
interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin
(IL)-2. In addition, Th17 cells seem to be involved leading to enhanced
synthesis of Th17 typical cytokines such as IL-23 and IL-17.
Several treatment options are currently available including
anti-inflammatory drugs, immunosuppressive drugs, biologics and other drugs to
manage specific symptoms. However, some patients respond only poorly to
established treatment options or, after an initial response, experience
flare-ups, and/or develop intolerable side effects.
The IMP IMU-838 (vidofludimus calcium) is a new compound that
selectively inhibits the human enzyme dihydroorotate dehydrogenase (DHODH).
DHODH plays a major role in the de-novo pyrimidine synthesis and is
specifically expressed at high levels in proliferating or activated
lymphocytes. IMU-838 selectively inhibits pyrimidine synthesis in activated
cells. The inhibition of nucleotide synthesis seems to be a promising approach
to treat IBD. Purine synthesis inhibitors are established products for the
long-term treatment of IBD. The DHODH inhibitor leflunomide, currently approved
for RA, was efficacious in small studies investigating Crohn*s Disease, but was
associated with diarrhea limiting its use in an IBD patient population.
Based on these data and the pharmacodynamics of vidofludimus, IMU-838
may represent a novel and efficacious oral treatment option for IBD patients.
Previous clinical studies with the predecessor drug 4SC-101 confirmed that
vidofludimus may be beneficial in patients with steroid-dependent IBD. Trial
P2 IMU 838 CD evaluates the efficacy and safety of the formulation IMU 838 in
patients with active CD.
Study objective
Primary 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)
Key secondary objective
• To determine the optimal dose of IMU-838 to induce endoscopic improvement in
patients with active CD
Study design
This is a phase 2, multicenter, randomized, double-blind,
placebo-controlled, parallel-group trial in patients with active CD with an
option for open-label treatment extension. The trial includes a screening
period, a blinded treatment (BT) period and an optional open-label extension
(OLE) period.
Patients will undergo 2 Screening visits for enrollment criteria.
The BT period will be a multicenter, randomized, double-blind,
placebo-controlled trial. It comprises an induction treatment phase of 14 weeks
and an extended treatment phase of 24 weeks (total 38 weeks BT).
A total of approximately 258 eligible patients with active CD will be
randomized 2:1:2 to placebo, 30 mg/day IMU-838, and 45 mg/day IMU-838.
After completion of the BT period, patients with no major protocol
deviation that in the investigator*s assessment may be relevant to patient
compliance in the OLE period, no medically relevant safety issues (as assessed
by the investigator) related to the IMP or the trial procedure, and no
significant non-compliance (as assessed by the investigator) will have the
option to enter the OLE period. Patients who discontinue the BT period
prematurely may also continue with open-label treatment, if they are eligible
based on the additional inclusion and exclusion criteria for the OLE period.
During the OLE, all patients will receive 30 mg/day IMU-838. Blinding of the
randomized treatment assignment during the BT period will be maintained for
patients entering the OLE period. The OLE period is optional.
Intervention
Blinded treatment (BT) period:
On Day 0, approximately 258 eligible patients will be randomized 2:1:2 to
placebo, 30 mg/day IMU 838, and 45 mg/day IMU 838. Randomization will be
stratified by prior use of biologics and current use of corticosteroids. The
proportion of patients who previously received biologics will be limited to
approximately 80% of all included patients.
All patients will receive only half of their assigned dose (1 tablet/day)
during the 1st week and continue with the full dose starting on Day 7 (2
tablets/day once daily). Clinic visits during the BT period will be scheduled
at Day 0, Day 7 (Week 1), at Week 2, and then every 28 days (every 4 weeks)
until Week 38.
The extended treatment phase will start after Week 14 and will continue
for 24 weeks. At Week 38 (end of BT period, EoBT), patients who completed all
Week 38 assessments, including an ileocolonoscopy, will have the option to
continue into the OLE period subject to additional inclusion and exclusion
criteria.
Open-label extension period:
Patients may enter the OLE period if they either completed the BT period (and
performed EoI and EoBT ileocolonoscopies), or, if they discontinued the BT
period prematurely, who will have completed at least 10 weeks of blinded
treatment, have at least 2 valid full CDAI, CDAI PRO-2 assessments, and
completed the EoI ileocolonoscopy (and an additional EoBT ileocolonoscopy, if
the EoI ileocolonoscopy was performed more than 14 weeks before the time of
discontinuation).
Study burden and risks
IMU-838 can reduce the tubular uptake of uric acid in the kidneys, leading to
an increase in urinary urinary acid excretion. Increased uric acid can in turn
result in microcrystallization of uric acid in acid urine and can lead to the
appearance of red blood cells in the urine. Various risk mitigation measures
for urinary events have been implemented in this study.
There is potential for the colonoscope to injure the intestinal wall, causing
perforation, infection or bleeding.
Side effects of IMU-838:
To date, around 300 patients have received a drug that is very similar to
IMU-838 and that contains the same active substance as IMU-838 (vidofludimus).
The most frequent adverse reaction reported by these patients was headache.
Other commonly reported illnesses or side effects were: nasopharyngitis (common
cold), urinary tract infection, diarrhea, upper abdominal pain and nausea.
Preliminary results from 2 studies in which 52 healthy individuals were treated
with IMU-838 are also available and the most frequently reported disease / side
effect was a cold. Other reported illnesses / side effects were flatulence,
increased red blood cell protein in urine, headache, soft stools, fatigue,
increased lipase (protein involved in fat metabolism) and flank pain. It is not
yet known whether these diseases and side effects are all related to the use of
IMU-838 or whether they occurred after placebo.
At high doses of IMU-838, much higher than those used in this study, cases of
increased numbers of red blood cells in urine were observed. However, this
unpleasant effect is not expected at doses used in this study. The urine will
be closely monitored for the presence of red blood cells.
Am Kopferspitz 19
Planegg-Martinsried 82152
DE
Am Kopferspitz 19
Planegg-Martinsried 82152
DE
Listed location countries
Age
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 IMP to avoid
exposure of the fetus to the IMP
11 Ability to understand and comply with trial procedures and restrictions
12 Written informed consentEXTENDED TREATMENT PHASE
1 At least symptomatic response at Week 14, defined as improvement in AP-CDAI
or SF CDAI scores of at least 30%, and both scores not worse than at Baseline
CRITERIA FOR SWITCHING FROM BLINDED TREATMENT TO OLE
1 Completion of at least 10 weeks of blinded treatment
2 Completion of a post-baseline ileocolonoscopy (either as EoI or EoBT
ileocolonoscopy) in the last 14 weeks before switching to OLE
a if discontinuing the induction treatment phase at Week 10 or be-tween Week 10
and Week 14, a complete EoI visit must be per-formed at the time of
discontinuation, including EoI ileocolonos-copy, or
b if discontinuing the extended treatment phase before Week 38, a complete EoBT
examination must be performed; however, EoBT ileocolonoscopy will only be
required if the EoI ileocolonoscopy was performed more than 14 weeks before the
time of discontinuation
3 At least 2 valid assessments of the full CDAI, SF-CDAI and AP-CDAI scores
post Baseline.sfSectie
Exclusion criteria
BT-period
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 vaccineOTHER 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 cancerTHERAPY 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 (at <=5 mg/day) and budesonide (at <=9
mg/day) unless they have been used at a stable dose for at least 2 weeks before
randomization
26 Oral aminosalicylates (e.g. mesalazines) <=4 g/day unless they have been used
at a stable dose for at least 3 weeks before randomization
27 Use of biologics as follows:
a anti-TNFα antibodies (infliximab, adalimumab, golimumab, certolizumab pegol,
including their biosimilars, if available) within 4 weeks before randomization
b vedolizumab and ustekinumab within 8 weeks before randomization
28 Use of the DHODH inhibitors leflunomide or teriflunomide within 6 months
before randomization
29 Any use of natalizumab (Tysabri*) within 12 months before randomization
30 Use of the following concomitant medications is prohibited at Screening
Visit S1 and throughout the duration of the trial:
a any medication known to significantly increase urinary elimination of uric
acid, in particular lesinurad (Zurampic*) as well as uricosuric drugs such as
probenecid
b active treatments for any malignancy, in particular irinotecan, paclitaxel,
tretinoin, bosutinib, sorafinib, enasidenib, erlotinib, regorafenib, pazopanib
and nilotinib
c any drug significantly restricting water diuresis, in particular vasopressin
and vasopressin analogs
d Rosuvastatin at doses >10 mg/dayPlease refer to protocol for information
on general exclusion criteria and exclusion criteria during OLE period.laatste
toed
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001895-39-NL |
| CCMO | NL69011.018.19 |