Study Objectives:Primary Objective: InductionTo evaluate the efficacy of cobitolimod treatment compared to placebo in inducing clinical remission, in participants with moderate to severe active left-sided UC.Secondary Objectives: Induction• To…
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Condition
- Other condition
Synonym
Health condition
inflammatory bowel disease
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Endpoint: Induction Study
Proportion of participants with clinical remission at I-week 6, defined by the
3-component Mayo score, i) rectal bleeding of 0, ii) stool frequency of 0 or 1
(with at least one (1) point decrease from I-week 0 if 1 at I-week 0), and iii)
endoscopic score of 0 or 1.
Primary Efficacy Endpoint: Maintenance Study
Proportion of participants with clinical remission at M-week 45, defined by the
3-component Mayo score, i) rectal bleeding of 0, ii) stool frequency of 0 or 1
(with at least one (1) point decrease from I-week 0 if 1 at I-week 0), and iii)
endoscopic score of 0 or 1.
Secondary outcome
Key Secondary Efficacy Endpoints: Induction Study
• Proportion of participants with endoscopic improvement at I-week 6 defined by
endoscopic subscore of 0 or 1.
• Proportion of participants with symptomatic remission at I-week 6 defined by
subscores, i) rectal bleeding of 0, ii) stool frequency of 0 or 1 (with at
least one (1) point decrease from I-week 0 if 1 at I-week 0).
Key Secondary Efficacy Endpoints: Maintenance Study
• Proportion of participants with endoscopic improvement at M-week 45.
• Proportion of participants with clinical remission at M-week 45 and
steroid-free for at least 8 weeks prior.
• Proportion of participants with clinical remission at M-week 45 among those
who achieved clinical remission at I-week 6.
• Proportion of participants with symptomatic remission at M-week 45.
Other endpoints are described in the main protocol.
Safety Endpoints
• incidence of AEs
• incidence of SAEs
• vital signs
• physical examination
• laboratory findings
Background summary
Background and Rationale: Cobitolimod is a fully synthetic DNA-based 19-mer
ODN. The drug functions as an immunomodulatory agent by targeting the TLR9
present in immune cells or on the surface of epithelial cells. These immune
cells (e.g., B cells, macrophages and plasmacytoid dendritic cells) reside in
high abundance on mucosal surfaces, such as colonic and nasal mucosa.
Cobitolimod will be rectally administered at the site of inflammation as a 50
mL enema, placing the drug in close contact with a high number of intended
target cells in an area rich in TLR9-expressing cells. Binding of the TLR9 by
cobitolimod triggers the cells to produce anti-inflammatory cytokines, such as
IL10, which are believed to be important for the clinical effect of
cobitolimod.
Based on data from non-clinical studies and five clinical studies, cobitolimod
is safe and well tolerated in the treatment of UC.
In the completed phase IIb study, CSUC-01/16 CONDUCT, significantly more
patients who received two administrations of cobitolimod 250 mg (2x 250 mg) 3
weeks apart achieved clinical remission at I-week 6 compared with patients who
received placebo. The results in several clinically relevant secondary
endpoints supported the efficacy of the 2 x 250 mg dose, which was the highest
dose of cobitolimod used in the study.
The full phase III programme for cobitolimod in the treatment of moderate to
severe UC will include two induction studies (induction 1 and induction 2
study) and one maintenance study. The first protocol (this protocol) will cover
the induction 1 study and the maintenance study. The second induction study
(induction 2 study) will be developed as a separate protocol. The maintenance
study will include participants from both the induction 1 and induction 2
studies.
In the current phase III study, CSUC-01/21 CONCLUDE, the 250 mg dose
(administered twice 3 weeks apart) has been selected for induction treatment
based on its demonstrated efficacy in the CSUC-01/16 CONDUCT study. However,
since the demonstrated efficacy was observed for the highest dose of
cobitolimod used in that study, it is possible that a dose higher than 250 mg
could provide additional efficacy. Therefore, a 500 mg dose (administered twice
3 weeks apart) will be explored as an additional active study arm for induction
treatment in this study in an adaptive design. The selection of the cobitolimod
500 mg dose is justified by previous safety data and toxicology studies. The
two active dose arms will be evaluated for induction treatment in induction
study 1 whereby only the *winning dose* will be continued after the interim
analysis and evaluated for confirmatory efficacy versus placebo at I-week 6.
Participants in both active dose arms will be evaluated for safety.
Participants responding to the winning dose at I-week 6 will be re-randomised
to maintenance treatment with the winning dose or with placebo.
Study objective
Study Objectives:
Primary Objective: Induction
To evaluate the efficacy of cobitolimod treatment compared to placebo in
inducing clinical remission, in participants with moderate to severe active
left-sided UC.
Secondary Objectives: Induction
• To evaluate the safety and tolerability of cobitolimod compared to placebo.
• To evaluate the efficacy of cobitolimod treatment compared to placebo in
clinical symptoms, endoscopy and histology endpoints.
• To evaluate the efficacy of cobitolimod treatment compared to placebo in
other secondary endpoints.
Exploratory Objectives: Induction
• To explore the efficacy of cobitolimod treatment compared to placebo in other
exploratory endpoints.
Primary Objective: Maintenance
To evaluate the efficacy of cobitolimod maintenance treatment compared to
placebo in inducing or maintaining clinical remission, in participants with
clinical response at I-week 6 after induction treatment with cobitolimod.
Secondary Objectives: Maintenance
• To evaluate the safety and tolerability of cobitolimod compared to placebo.
• To evaluate the efficacy of cobitolimod maintenance treatment compared to
placebo in clinical symptoms, endoscopy and histology endpoints.
• To evaluate the efficacy of cobitolimod maintenance treatment compared to
placebo in other secondary endpoints.
• To evaluate HRQoL and health economics.
Exploratory Objectives: Maintenance
To explore the efficacy of cobitolimod maintenance treatment compared to
placebo in other efficacy endpoints.
Study design
Study Design:
This phase III protocol includes an induction and a maintenance study. These
are randomised, double-blind, placebo-controlled, parallel-group, multicentre
studies of cobitolimod in participants with moderate to severe active
left-sided UC who demonstrate an inadequate response to or intolerance of
conventional, biological (infliximab, adalimumab, golimumab, vedolizumab,
ustekinumab), JAK-inhibitor (tofacitinib) or other approved advanced therapy
for UC.
Induction Study
Induction study 1 will have an adaptive design in two stages. Stage 1 will
explore the efficacy of two different doses of cobitolimod, 250 mg and 500 mg,
with placebo as a control. In stage 2, the study will drop-the-loser and
continue with the winning dose of cobitolimod. The primary objective of the
induction study is to confirm a superior efficacy compared to placebo of the
winning dose of cobitolimod.
In stage 1, participants will be randomly assigned in a 1:1:1 allocation to
receive two rectal doses (3 weeks apart) of cobitolimod 250 mg, cobitolimod 500
mg, or placebo. When 44 participants in each arm have eligible efficacy data
for the primary endpoint at I-week 6, an interim analysis will be performed.
This will give guidance which dose (cobitolimod 250 mg or 500 mg) will be
dropped, and which dose will be used in stage 2 of this induction study.
The interim analysis will also include a futility analysis.
In stage 2, additional 154 participants per remaining arm will be recruited and
randomly assigned in a 1:1 allocation to the winning dose of cobitolimod or to
placebo. Existing participants in the losing dose cobitolimod dose arm will be
followed up for safety but will not be included in the final efficacy
evaluation at I-week 6.
Randomisation in stage 1 and stage 2 will be stratified for concomitant use of
GCS treatment and for previous treatment with biologics, JAK-inhibitors or
other approved advanced therapy. Induction study clinic visits will take place
at screening, I-week 0, I-week 3 and I-week 6. A full colonoscopy will be done
during screening, with a maximum of 10 days between colonoscopy and
randomisation. At I-week 6 a flexible sigmoidoscopy will be performed.
Endoscopies will be centrally read.
Participants will self-administer the study drug at clinic under supervision of
study staff, to ensure that participants can manage to self-administer the
study drug at home during the maintenance study.
Maintenance Study
Participants who achieve clinical response at I-week 6 after starting induction
treatment will be eligible for the maintenance study. Clinical response is
defined by a decrease in the 3-component Mayo score (rectal bleeding, stool
frequency, and endoscopy) of at least two (2) points and at least 35% from
I-week 0 with either a decrease in the rectal bleeding subscore of at least one
(1) point or a rectal bleeding subscore of 0 or 1. Eligible participants
(I-week 6 responders) will be re-randomised in a 1:1 allocation to the winning
dose of cobitolimod or to placebo, administered once every 3 weeks.
Participants who were treated with placebo or the losing dose in the induction
study who meet the responder*s criterion at I-week 6 assessment will continue
into the maintenance study but will be excluded from the efficacy analysis.
At least 250 responders to the winning dose of cobitolimod will be enrolled
into the maintenance study from the induction 1 study and the subsequent
induction 2 study (which is outside the scope of this protocol).
Participants in the maintenance study will be scheduled for clinic or virtual
visits at M-weeks 0, 7, 15, 23, 31, 39 and 45 (see SoA).
At the first administration occasion in the maintenance study (following
re-randomisation), the study intervention will be self-administered at the
clinic by the participant under supervision of study staff. During all
subsequent administration occasions, the study intervention will be
self-administered by the participant at home every third week.
Evaluation and follow-up of participants will be performed at all visits. If
the participant*s disease deteriorates or does not improve, it is at the
discretion of the investigator to judge if an alternative treatment is needed,
and if so to take the necessary action.
Intervention
Investigational Therapy and Treatment:
In the induction study 1, cobitolimod 250 mg or 500 mg or placebo will be
self-administered with a rectal enema at I-week 0 and I-week 3, under
supervision of study staff.
The first dose of study intervention in the maintenance study (M-week 0) will
be self-administered at clinic under supervision of study staff. All subsequent
doses will be self-administered at home.
The primary endpoint for induction will be assessed after 6 weeks. The primary
endpoint for maintenance will be assessed after 46 weeks of maintenance
treatment (approximately 52 weeks from induction study, I-week 0).
Safety evaluation and disease monitoring will be performed at each visit after
the first dose.
Reference Therapy:
Placebo is the same aqueous solution as the drug product apart from
cobitolimod.
Study burden and risks
Abdominal Pain 2.4%
Headache 11.3%
Anaemia/Haemoglobin decreased 4.6%
Haemorrhoids 1.2%
Arthralgia (joint pain) 1.2%
Nausea 2.2%
Blood in urine 2.2%
Protein in urine 1.4%
Common Cold/Upper Respiratory Infections 7.7%
Fever 3.1%
CRP increased (blood test marker for inflammation in the body) 1.7%
Rash 2.9%
Diarrhoea 1.2%
Ulcerative Colitis, Worsening 7.7%
Dyspepsia (upset stomach) 1.9%
Vomiting 1.2%
If new information about side effects for the study drug becomes known, you
will be informed about them.
You can experience the following discomforts from the study procedures:
• Taking blood samples: This involves a needle prick which can feel unpleasant
and painful and can lead to a transient bruise, dizziness, and rarely
haematoma, infections, and nerve damage.
• Endoscopy and biopsies: Possible complications include infection, perforation
(piercing or tearing) of the bowel or excessive bleeding.
You can feel discomfort during and for a little bit after the procedure as air
is inflated, and water is flushed for better visibility during the examination.
• Investigational treatment administration: you can feel discomfort during and
for a little bit after the administration of the enema.
• ECG: Patches may cause skin reactions such as redness, itching and hair loss
associated with the placement of the ECG electrodes.
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Listed location countries
Age
Inclusion criteria
Inclusion Criteria: Induction
1. Male or female >= 18 years of age.
2. Established diagnosis of UC, with minimum time from diagnosis of at least 3
months before screening visit 1b.
3. Moderate to severe active left-sided UC (disease should extend 15 cm or more
above the anal verge and not beyond the splenic flexure) determined by a
3-component Mayo score of 5 to 9 with an endoscopic subscore >=2 (in sigmoid or
descending segments) assessed by central reading of endoscopy, and with stool
frequency and rectal bleeding subscores, assessed by eDiary, each >=1.
4. Have inadequate response, loss of response or be intolerant of at least one
of the following treatments:
a. Oral GCS
b. AZA/6-MP
c. Biologics, JAK-inhibitors, or other approved advanced therapies for UC
5. Allowed to receive a therapeutic dose of the following UC drugs during the
study:
a. Oral GCS therapy (<=20 mg prednisone or equivalent/day) provided that the
dose has been stable for 2 weeks prior to visit 1b, or oral Budesonide MMX®
therapy (9 mg/day) initiated at least 8 weeks before visit 1b, provided that
the dose has been stable for 2 weeks prior to visit 1b.
b. Oral 5-ASA/SP compounds, provided that the dose has been stable for 2 weeks
prior to visit 1b and initiated at least 8 weeks before visit 1b.
c. AZA/6-MP provided that the dose has been stable for 8 weeks prior to visit
1b and initiated at least 3 months before visit 1b.
6. Ability to understand the treatment, willingness to comply with all study
requirements, and ability to provide informed consent.
Inclusion Criteria: Maintenance
Participants are eligible to be included in the maintenance study if they have
achieved clinical response at I-week 6 and have adhered to the protocol
procedures of the induction study.
Clinical response is defined by a decrease in the 3-component Mayo score
(rectal bleeding, stool frequency, and endoscopy) of at least two (2) points
and at least 35% from I-week 0 with either a decrease in the rectal bleeding
subscore of at least one (1) point or a rectal bleeding subscore of 0 or 1.
Exclusion criteria
Exclusion Criteria: Induction
1. Suspicion of differential diagnosis such as Crohn*s enterocolitis, ischaemic
colitis, radiation colitis, indeterminate colitis, infectious colitis,
diverticular disease, associated colitis, microscopic colitis, massive
pseudopolyposis or non-passable stenosis.
2. Acute fulminant UC, toxic megacolon and/or signs of systemic toxicity.
3. UC limited to the rectum (disease extending <15 cm above the anal verge)
or extending beyond the splenic flexure.
4. Have failed treatment with more than three advanced therapies (infliximab,
adalimumab, golimumab, vedolizumab, ustekinumab or tofacitinib) of two
different therapeutic classes (anti-TNF, anti-integrins, anti-IL12/23,
JAKinhibitors, or other approved advanced therapies for UC).
5. Have had surgery for treatment of UC.
6. History of malignancy, unless treated with no relapse of the disease and >= 5
years since last treatment (cured) or treated (cured) basal cell or squamous
cell in situ carcinoma.
7. History or presence of any clinically significant disorder that, in the
opinion of the investigator, could impact on the participant*s ability to
adhere to the protocol and protocol procedures, or would confound the study
result or compromise participant safety.
8. Concomitant treatment with cyclosporine, methotrexate, tacrolimus, or
advanced therapies such as infliximab, adalimumab, golimumab, vedolizumab,
ustekinumab or tofacitinib, or similar immunosuppressants and immunomodulators
at enrolment.
Any prior treatment with such drugs must have been discontinued at least 8
weeks prior to visit 1b (except for ustekinumab, which must have been
discontinued at least 12 weeks prior to visit 1 b) or have non-measurable serum
concentration levels.
9. Treatment with rectal GCS, 5-ASA/SP or tacrolimus within 2 weeks before
visit 1b.
10. Long-term treatment (>14 days) with antibiotics or NSAIDs within 2 weeks
prior to visit 1b (one short treatment regimen for antibiotics, occasional use
of NSAIDs and low dose NSAIDs as prophylactic therapy is allowed).
11. Serious known active infection including history of latent or active
tuberculosis, documented history of past or current tuberculosis, or living
with or having frequent close contact with people with active tuberculosis or
with a positive tuberculosis test according to current regulations for 12 weeks
preceding randomisation. Serious infections include, but is not limited to,
HIV, HBV, or HCV infections.
12. Gastrointestinal infections including positive Clostridium difficile stool
assay. (Local laboratory reports must be available in accordance with normal
clinic practice, to confirm that the current episode of disease exacerbation is
not due to infection).
13. Females who are lactating or have a positive serum pregnancy test during
the screening period.
14. Women of childbearing potential not using highly effective (failure rate
< 1%) contraceptive methods throughout the duration of the study.
15. Concurrent participation in another clinical study with investigational
therapy or previous use of investigational therapy within 5 half-lives and
within at least 30 days after last treatment of the experimental product prior
to enrolment.
16. Previous exposure to cobitolimod
Exclusion Criteria Maintenance:
Participants will not be eligible for the maintenance study if they are not
willing to comply with all further study requirements.
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 | EUCTR2021-002549-13-NL |
| CCMO | NL80916.091.22 |