This study has been transitioned to CTIS with ID 2024-511472-32-00 check the CTIS register for the current data. Primary for Platform-Level Exploratory Analysis1. To evaluate whether treatment with IL-23 inhibitors is superior to adult placebo in…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary parameters for Platform-Level Exploratory Analysis
• Proportion of participants achieving clinical remission (PCDAI) at Week 52 AND
• Proportion of participants achieving endoscopic response (SES-CD) at Week 52
Primary global parameters
• Clinical remission at Week 52 (defined as PCDAI score <=10)
• Endoscopic response (>=50% reduction from SES-CD score at baseline) at Week 52
Secondary outcome
Global parameters
• Clinical response (decrease from baseline/LOR reference in the PCDAI score
>=12.5; total score <=30) at Week 12
• Clinical response (PCDAI) at Week 52
• Clinical remission (PCDAI) at Week 12
• Endoscopic remission (SES-CD) at Week 52
• Corticosteroid-free clinical remission at Week 52 (defined as PCDAI score <=10
at Week 52 and not receiving corticosteroids for at least 90 days before Week
52)
• Sustained clinical remission at Weeks 12, 24, and 52 (defined as PCDAI <=10 at
each of these timepoints)
• Clinical remission by PRO at:
* Week 12
* Week 52
* Week 12 and Week 52
• Serum mirikizumab concentration during induction from Week 0 through Week 12
• Serum mirikizumab concentration during maintenance (at least Ctrough)
• Change from baseline at Weeks 12, 24, and 52 in:
* Weight
* Weight percentiles and z-scores
* Height
* Height percentiles and z-scores
* Height Velocity
• AEs, including SAEs
• Clinical remission at Week 52 (defined as PCDAI score <=10)
• Endoscopic response (>=50% reduction from SES-CD score at baseline) at Week 52
Background summary
The basic pathogenesis of CD is similar in pediatric and adult populations (Van
Limbergen 2008; Vernier-Massouille 2008). Both adult and pediatric CD can
affect any portion of the intestinal tract with focal, asymmetric, transmural,
and granulomatous inflammation and is characterized by transmural infiltration
of lymphocytes and macrophages, granulomas, fissuring ulceration, and
submucosal fibrosis (Gajendran 2018; Rosen 2015; Torres 2017). Most commonly,
children have ileocolonic involvement, and approximately one-third of children
have upper tract involvement as well (Conrad 2017). In addition to the clinical
similarities between adult and pediatric CD (eg, natural history, response to
existing therapeutics), there is strong molecular genetic support for
extrapolation of results in adults with CD to children. CD in both adults and
children appears to result from complex interactions between evolving
environmental changes induced by societal progress, predisposing genetic
mutations, gut microbiota, and immune defense mechanisms (Kugathasan 2007).
The treatment of pediatric CD generally follows the same paradigms that are
used to treat adult disease. The current standard of care involves
anti-inflammatory therapeutic approaches, which include, corticosteroids,
immunomodulatory agents (AZA, 6-MP, MTX), and TNF antagonist
therapies. Per recent evidence- and consensus-based recommendations, the
overall goals of treatment are similar in adults and children with CD: to
induce short-term clinical response and to maintain disease remission with
endoscopic response (Turner 2021). Responses to treatment are
generally similar in adult and pediatric patients with CD based on available
data (Van Limbergen 2008; Vernier-Massouille 2008).
Therefore, as in adults, there is a significant unmet medical need for
additional safe and efficacious treatment options for children with CD. The
lifelong course of the disease, and the lack of durable treatment highlights
the need for additional options with a favorable benefit-risk profile.
The hypothesis for the platform-level exploratory analysis is that treatment
response of pediatric
participants with moderately to severely active CD treated with an IL-23
inhibitor is superior to
that of adult participants with moderately to severely active CD administered
placebo (based on adult placebo historical control data). The totality of
evidence determining efficacy will be based on the intervention cohort-specific
analyses with support of the exploratory platform analyses.
Study objective
This study has been transitioned to CTIS with ID 2024-511472-32-00 check the CTIS register for the current data.
Primary for Platform-Level Exploratory Analysis
1. To evaluate whether treatment with IL-23 inhibitors is superior to adult
placebo in achieving clinical remission and endoscopic response in pediatric
participants with moderately to severely active CD at Week 52 who do not
require modification of IP regimen, IP rescue therapy, or non-IP rescue therapy
Abbreviations: CD=Crohn*s disease; IL=interleukin, IP=investigational product;
PCDAI=Pediatric Crohn*s Disease Activity pic Score for Crohn*s Disease.
Non-IP rescue therapy is CD medications not including study intervention
(guselkumab or mirikizumab) as specified in the applicable ISA.
Primary global
2. To evaluate the clinical and endoscopic efficacy of mirikizumab in pediatric
participants with CD at the end of maintenance therapy among participants who
were in clinical response to mirikizumab at Week 12
Secondary
• To evaluate the clinical efficacy of mirikizumab in pediatric participants
with CD
• To evaluate the efficacy of treatment with mirikizumab in clinical remission
by PROb at Week 12 and/or Week 52
Note: Depending on the participant*s age, can be PRO or ObsRO
• To evaluate the PK and immunogenicity of mirikizumab in pediatric
participants with CD
• To assess the impact of mirikizumab therapy on growth
• To evaluate the safety of mirikizumab in pediatric participants with CD
• To evaluate the efficacy of treatment with mirikizumab in participants who
are assigned at Week 12 to q4w maintenance therapy and do not receive
non-investigational product (IP)c rescue therapy
• To further evaluate the clinical efficacy of mirikizumab in pediatric
participants with CD
• To evaluate the efficacy of treatment with mirikizumab in inducing endoscopic
remission at Week 52
• To assess the fistula response rate of mirikizumab therapy
• To assess the impact of mirikizumab therapy on CD-related QoL
• To explore serum and fecal biomarkers in pediatric participants with
moderately to severely active CD
• To evaluate the efficacy of treatment with mirikizumab in inducing histologic
remission at Week 52
Study design
This is a Phase 3 multicenter, randomized, 2-arm, intervention platform program
to investigate the efficacy, safety, and PK of 2 different IL-23 inhibitors in
pediatric CD. The platform program will use a treat-through* design and will
assess induction and maintenance efficacy of 2 different IL-23 inhibitors
guselkumab [JRD] or mirikizumab [Lilly]), with participants being followed from
randomization through the safety follow-up visit for participants who do not
enter the LTE (including early terminators), or Week 52 for patients who enter
the LTE.
The 2 ISAs have separate sample size requirements (ranging from approximately
90 to 120 participants) to provide additional descriptive efficacy and safety
data for the specific intervention, which are described in the applicable ISA.
The platform-level exploratory analysis is powered at N=50 randomized
participants per intervention-specific platform cohort. Thus, the platform
analysis set will have an adequate sample with at least 100 randomized
participants (ie, at least 50 per intervention-specific platform cohort) to
control for an acceptably low false positive and false negative rate for the
platform-level coprimary endpoints.
The study population includes pediatric participants (2 to <18 years of age)
with moderately to severely active CD (defined by a baseline PCDAI score >30)
who have an inadequate response to, LOR to, or are intolerant to non-biologic
therapy for CD (biologic-naïve, Bio-NF), and/or those who failed biologic
and/or advanced therapy for CD (eg, biologic/JAK inhibitor-failed, Bio-IR).
Screening is to be performed prior to randomization to minimize imbalances
between the intervention-specific platform cohorts in the enrolled participant
populations due to differences in screen failures (if randomization to the
intervention-specific platform cohort occurred prior to screening). If only 1
intervention cohort is open, participants will be assigned to that intervention
cohort. In addition, stratification for the randomization of intervention
cohort assignment to maintain comparable populations across
intervention-specific platform cohorts will be used. Stratification factor(s)
include prior biologic/JAK use and age (2 to <6, 6 to <12, 12 to <18 years of
age).
Study periods will be as follows:
• The screening period will be up to 6 weeks.
• A 12-week induction period.
• A maintenance period from Week 12 to Week 52.
• A safety follow-up period as specified in the applicable ISA.
Study burden and risks
The clinical benefit of mirikizumab, an IL-23 antagonist, has been shown in a
limited dataset in adults with moderately to severely active CD, and is being
further evaluated in an ongoing Phase 3 study. A compound with a similar
mechanism of action affecting the same pathway, ustekinumab (an antagonist of
IL-12 and IL-23), has been approved for the treatment of CD in adults.
Ustekinumab has also been studied in a Phase 1 pediatric CD study,
CNTO1275CRD1001 (UniStar), and in an ongoing pediatric CD Phase 3 study
(CNTO1275CRD3004; UNITI, Jr). In CNTO1275CRD1001, serum ustekinumab
concentrations observed in the overall pediatric CD population were generally
comparable to those observed in the reference adult CD population (with lower
serum concentrations in participants with body weight <40 kg). Also, at Week 8,
ustekinumab induction treatment resulted in meaningful improvements in the
efficacy endpoints evaluated, including PCDAI-based clinical response and
clinical remission (Rosh 2021).
While the CNTO1275CRD1001 results with a compound with a similar mechanism of
action are suggestive that mirikizumab should be effective in pediatric CD, the
clinical benefit of mirikizumab remains to be seen in pediatric participants as
the clinical development program is ongoing. While it is possible that
participants in this study may not benefit from the study intervention, the
results from the GALAXI 1 IA suggests the clinical benefit of mirikizumab. The
sponsor anticipates that pediatric participants with CD may benefit from
treatment with mirikizumab. Participants may also have some benefit from the
participation in a clinical study irrespective of receiving study intervention,
due to regular visits and assessments monitoring their overall health. Lastly,
while not directly benefiting the participant, results from this clinical study
will inform on the overall safety and efficacy of mirikizumab in treating
moderately to severely active CD in pediatric participants ages 2 to <18, which
would benefit other pediatric patients with CD.
893 S Delaware St. IN 46225
Indianapolis IN 46285
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893 S Delaware St. IN 46225
Indianapolis IN 46285
US
Listed location countries
Age
Inclusion criteria
1. 2 to <18 years of age, inclusive (at the time of consent for screening).
2. Medically stable based on physical examination, medical history, and vital
signs
performed at screening. Medically stable based on clinical laboratory tests
performed at
screening.
3. Have a diagnosis of CD or fistulizing CD, with active colitis, ileitis, or
ileocolitis,
confirmed at any time in the past by clinical, endoscopic, and histologic
criteria.
Diagnosis based on prior surgical resection and histology is also acceptable.
Radiographic
findings may provide supportive evidence.
4. Have moderately to severely active CD (as defined by a screening PCDAI score
>30).
5. Have endoscopy with evidence of active CD defined as SES-CD score >=6 (or >=4
for
participants with isolated ileal disease) within 4 weeks of receiving study
intervention
at Week 0.
6. Body weight >=10 kg at the time of consent for screening.
Please refer to the Master protocol for more inclusion criteria, section 5.1.
Exclusion criteria
1. Has complications of CD such as symptomatic strictures or stenosis, short
gut syndrome, or any other manifestation that might be anticipated to require
surgery, that could preclude the use of the PCDAI to assess response to therapy
or would possibly confound the ability to assess the effect of the treatment.
Of note, surgical procedures related to fistula treatment are not necessarily
exclusionary; discuss with medical monitor.
2. Currently has or is suspected to have an abscess. Recent cutaneous and
perianal abscesses are not exclusionary if drained and adequately treated at
least 3 weeks prior to Week 0, or 8 weeks prior to Week 0 for intra-abdominal
abscesses, provided that there is no anticipated need for any further surgery.
3. Has had any kind of bowel resection within 26 weeks or any other
intra-abdominal surgery within 12 weeks of baseline.
4. Presence of a stoma, ileoanal pouch, or ostomy.
5. Has high grade dysplasia, history of or current evidence of polypoid or
non-polypoid dysplasia, or any adenoma that has not been removed.
Please refer to the Master protocol for more exclusion criteria, section 5.2
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 |
|---|---|
| EU-CTR | CTIS2024-511472-32-00 |
| EudraCT | EUCTR2022-000811-29-NL |
| CCMO | NL83188.056.22 |