A Phase 3 Study of the Efficacy, Safety, and Pharmacokinetics of Ustekinumab as Open-label Intravenous Induction Treatment Followed by Randomized Double-blind Subcutaneous Ustekinumab Maintenance in Pediatric Participants With Moderately to Severely Active Crohn's Disease
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Enrollment
- 101
- Locations
- 102
- Primary Endpoint
- Number of Participants with Clinical Remission at Maintenance Week 44
Study Overview
Brief Summary
The purpose of this study is to evaluate the efficacy of ustekinumab dosing in inducing clinical remission (Global) and in maintaining clinical remission (US); to evaluate the safety profile and ustekinumab exposure (pharmacokinetics [PK]) in pediatric participants with moderately to severely active Crohn's disease.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Masking Description
Induction period is an open-label period and maintenance period is a double-blind period.
Eligibility Criteria
- Ages
- 2 Years to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Have Crohn's disease or fistulizing Crohn's disease with active colitis, ileitis, or ileocolitis, confirmed at any time in the past by endoscopy and histology
- •Must have moderately to severely active Crohn's disease (as defined by a baseline Pediatric Crohn's Disease Activity Index [PCDAI] score greater than [>] 30); have ileocolonoscopy with evidence of active Crohn's disease defined as presence of ulceration (which is equal to Simple Endoscopic Score for Crohn's disease [SES-CD] score greater than or equals to [>=] 3) during screening into this study. The ileocolonoscopy procedure must occur within approximately 3 weeks prior to the administration of study intervention at Week 0 (Induction Period). A video ileocolonoscopy recorded within 3 months prior to the Week 0 (Induction Period) visit may be used in case of rescreening of a participant who had an ileocolonoscopy but failed the initial screening for another reason, on a case-by-case basis, after consultation with the sponsor. If unable to evaluate ulceration due to stricture or inadequate bowel preparation, at least one of the following criteria may instead be applied: an abnormal C-reactive protein (CRP) (> 0.3 milligram per deciliter [mg/dL] or 3.0 milligram per liter [mg/L] at screening) or; fecal calprotectin of >= 250 milligram per kilogram [mg/kg] or >= 250 microgram per gram [mcg/g] at screening
- •If receiving enteral nutrition, must have been on a stable regimen for at least 2 weeks prior to induction week 0 (Week I-0)
- •Females of childbearing potential must have a negative highly sensitive urine pregnancy test at screening and at Week I-0 prior to study intervention administration
Exclusion Criteria
- •Has complications of Crohn's disease 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 treatment with ustekinumab
- •Have a history of latent or active granulomatous infection, histoplasmosis, or coccidioidomycosis, or have had a nontuberculous mycobacterial infection prior to screening
- •Presence or history of any malignancy including presence or history of lymphoproliferative disease including lymphoma, or signs and symptoms suggestive of possible lymphoproliferative disease, such as lymphadenopathy of unusual size or location (example, nodes in the posterior triangle of the neck, infraclavicular, epitrochlear, or periaortic areas), and monoclonal gammopathy of undetermined significance, or clinically significant hepatomegaly or splenomegaly
- •Have a history of moderate or severe progressive or uncontrolled liver or renal insufficiency; or significant cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, psychiatric (including suicidality), or metabolic disturbances
- •Received an investigational intervention including any investigational vaccines or used an invasive investigational medical device within 3 months before the planned first dose of study intervention or is currently enrolled in an investigational study; receipt of an investigational vaccine for Coronavirus Disease 2019 (COVID-19) is not an automatic exclusion criterion
Arms & Interventions
Ustekinumab Subcutaneous (SC) Every 8 Weeks (q8w): Maintenance Period
Participants will receive SC administration of ustekinumab q8w based on BSA (mg/m^2) or weight-tiered induction dose (mg/kg) at maintenance weeks (Weeks M)-0, M-8, M-16, M-24, M 32, and M-40 and matching placebo at Weeks M-12 and M-36 to maintain the blind.
Intervention: Placebo (Drug)
Ustekinumab SC Every 12 Weeks (q12w): Maintenance Period
Participants will receive SC administration of ustekinumab q12w based on BSA (mg/m^2) or weight-tiered induction dose (mg/kg) at Weeks M-0, M-12, M-24, M-36 and matching placebo at Weeks M-8, M-16, M-32, and M-40 to maintain the blind.
Intervention: Placebo (Drug)
Open- Label Ustekinumab Intravenous (IV): Induction Period
All participants will receive a single IV administration of ustekinumab at induction Week 0 (I-0) based on body surface area (BSA) (milligram per meter square [mg/m^2]) or weight-tiered induction dose (milligram per kilogram [mg/kg]).
Intervention: Ustekinumab (Drug)
Ustekinumab Subcutaneous (SC) Every 8 Weeks (q8w): Maintenance Period
Participants will receive SC administration of ustekinumab q8w based on BSA (mg/m^2) or weight-tiered induction dose (mg/kg) at maintenance weeks (Weeks M)-0, M-8, M-16, M-24, M 32, and M-40 and matching placebo at Weeks M-12 and M-36 to maintain the blind.
Intervention: Ustekinumab (Drug)
Ustekinumab SC Every 12 Weeks (q12w): Maintenance Period
Participants will receive SC administration of ustekinumab q12w based on BSA (mg/m^2) or weight-tiered induction dose (mg/kg) at Weeks M-0, M-12, M-24, M-36 and matching placebo at Weeks M-8, M-16, M-32, and M-40 to maintain the blind.
Intervention: Ustekinumab (Drug)
Outcomes
Primary Outcomes
Number of Participants with Clinical Remission at Maintenance Week 44
Time Frame: Week 44 (Maintenance Period)
Number of participants with clinical remission in maintenance period will be assessed. This will be assessed among participants who are in clinical response at induction week-8 (I-8). Clinical remission is defined as having a PCDAI score \<= 10 points. PCDAI is an index used to measure disease activity of pediatric patients with Crohn's Disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdominal tenderness or mass, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease.
Number of Participants with AEs of Interest
Time Frame: Up to Week 74
Number of participants with AEs of interest (any newly identified malignancy, or case of active tuberculosis \[TB\], or opportunistic infection occurring after the first administration of study intervention\[s\]) will be reported.
Number of Participants with Abnormalities in Clinical Laboratory Parameters
Time Frame: Up to Week 52
Number of participants with abnormalities in clinical laboratory parameters (such as hematology and chemistry) will be reported.
Number of Participants with Reactions Temporally Associated with Intravenous (IV) Infusion (Induction Period)
Time Frame: Up to Week 8 (Induction period)
Number of participants with reactions temporally associated with IV infusion in induction period will be reported.
Number of Participants with Clinical Remission at Induction Week 8
Time Frame: Week 8
Number of participants with clinical remission in induction period will be assessed. Clinical remission is defined as having a Pediatric Crohn's Disease Activity Index (PCDAI) score less than or equal to (\<=) 10 points. PCDAI is an index used to measure disease activity of pediatric patients with Crohn's Disease assessing abdominal pain, stool frequency, patient functioning, hematocrit, erythrocyte sedimentation rate, albumin, weight, height, abdominal tenderness or mass, perirectal disease, and extraintestinal manifestations. It ranges from 0 to 100; higher scores indicate more active disease.
Number of Participants with Adverse Events (AEs)
Time Frame: Up to Week 74
An AE can be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational or non investigational) product, whether or not related to that medicinal (investigational or non investigational) product.
Number of Participants with Serious Adverse Events (SAEs)
Time Frame: Up to Week 74
A SAE is any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a suspected transmission of any infectious agent via a medicinal product; is medically important.
Number of Participants with AEs leading to Discontinuation of Study Intervention
Time Frame: Up to Week 74
Number of participants with AEs leading to discontinuation of study intervention will be reported.
Serum Ustekinumab Concentrations
Time Frame: Up to Week 52
Serum ustekinumab concentrations will be reported.
Number of Participants with Subcutaneous (SC) Injection-Site Reactions (Maintenance Period)
Time Frame: Up to Week 44 (Maintenance period)
Number of participants with SC injection-site reactions in maintenance period will be reported.
Global Outcome Measure: Percentage of Participants With Clinical Remission at Induction Week 8 (Week I-8)
Time Frame: Induction Week 8 (Week I-8)
Clinical remission was defined as a Pediatric Crohn's Disease Activity Index (PCDAI) score \<=10. The 11-item PCDAI covered five general disease activity domains: symptom history scores (3 items: abdominal pain, stool frequency, and general well-being); laboratory scores (3 items: hematocrit \[HCT\], erythrocyte sedimentation rate \[ESR\], Albumin); growth scores (2 items: weight and height); physical examination scores (2 items: abdomen and perirectal disease); and extraintestinal manifestations. The category of severity for each index item is assigned a score: 0=normal;5=mild abnormality; 10= severe abnormality. For hematocrit and erythrocyte SR, the maximum score =5. For albumin level, the maximum score = 10. All items were summed to derive the total score. The total PCDAI score ranged from 0 to 100, with higher scores indicating greater disease activity.
US-specific Outcome Measure: Percentage of Participants With Clinical Remission at Maintenance Week 44
Time Frame: Maintenance Week 44 (Study Week 52)
Clinical remission was defined as a Pediatric Crohn's Disease Activity Index (PCDAI) score \<=10. The 11-item PCDAI covered five general disease activity domains: symptom history scores (3 items: abdominal pain, stool frequency, and general well-being); laboratory scores (3 items: HCT, ESR, Albumin); growth scores (2 items: weight and height); physical examination scores (2 items: abdomen and perirectal disease); and extraintestinal manifestations. The category of severity for each index item was assigned a score: 0=normal;5=mild abnormality; 10= severe abnormality. For hematocrit and erythrocyte SR, the maximum score= 5. For albumin level, the maximum score= 10. All items were summed to derive the total score. The total PCDAI score ranged from 0 to 100, with higher scores indicating greater disease activity.
Global and US-specific Outcome Measures: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 44 (Study Week 52)
Number of participants with TEAEs were reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE did not necessarily have a causal relationship with the intervention. TEAEs were defined as AEs occurring at or after the initial administration of the study intervention.
Global and US-specific Outcome Measures: Number of Participants With Treatment-emergent Serious Adverse Events (TESAEs)
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 44 (Study Week 52)
Number of participants with TESAEs was reported. An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE did not necessarily have a causal relationship with the intervention. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly. TESAEs were defined as any SAE occurring at or after the initial administration of the study intervention.
Global and US-specific Outcome Measures: Number of Participants With AEs Leading to Discontinuation of Study Intervention
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 40 (Study Week 48)
Number of participants with AEs leading to discontinuation of study intervention were reported.
Global and US-specific Outcome Measures: Number of Participants With AEs of Special Interest (AESI)
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 44 (Study Week 52)
An AE was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An AE did not necessarily have a causal relationship with the intervention. AESI were defined as any newly identified malignancy, or case of active TB, or opportunistic infection occurring after the first administration of study intervention.
Global and US-specific Outcome Measures: Number of Participants With Abnormalities in Clinical Laboratory Parameters: Hematology
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 44 (Study Week 52)
Number of participants with abnormalities in clinical laboratory parameters (hematology) were reported. It included hemoglobin (Hb). Grades 0-4 were based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), where Grade 0 was normal, Grade 1 was mild, Grade 2 was moderate, Grade 3 was severe or medically significant but not immediately life-threatening, and Grade 4 was life-threatening consequences. Higher grades showed more severe abnormalities. Only abnormalities where atleast one participant had data are reported. Inc = increased, Dec= decreased.
Global and US-specific Outcome Measures: Number of Participants With Abnormalities in Clinical Laboratory Parameters: Chemistry
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 44 (Study Week 52)
Number of participants with abnormalities in clinical laboratory parameters were reported. It included chemistry measures: alanine aminotransferase (ALT), aspartate aminotransferase (AST),blood bilirubin (BB). Grades 0-4 were based on NCI-CTCAE version 5.0, where Grade 0 was Normal, Grade 1 was mild, Grade 2 was moderate, Grade 3 was severe or medically significant but not immediately life-threatening, and Grade 4 was life-threatening consequences. Higher grades showed more severe abnormalities. Only abnormalities where at least one participant had data are reported. Inc = increased, Dec= decreased.
Global and US-specific Outcome Measures: Number of Participants With Reactions Temporally Associated With Intravenous (IV) Infusion (Induction Period) and Subcutaneous (SC) Injection-Site Reactions (Maintenance Period)
Time Frame: Induction Period: From induction Week 0 up to induction Week 8; Maintenance Period: From Maintenance Week 0 (Study Week 8) up to Maintenance Week 44 (Study Week 52)
Number of participants with reactions temporally associated with intravenous (IV) infusion (Induction Period) and subcutaneous (SC) Injection-Site Reactions (Maintenance Period) were reported.
Global and US-specific Outcome Measures: Serum Ustekinumab Concentrations
Time Frame: Induction Period: Week 0 (Pre-infusion), Week I-0 (1-hour post infusion), Week I-3, Week I-6, and Week I-8; Maintenance Period: Week M-4, Week M-8, Week M-12, Week M-16, Week M-24, Week M-32, Week M-36 and Week M-44
Serum ustekinumab concentrations were reported.
Secondary Outcomes
- Number of Participants with Clinical Remission as Assessed by short Pediatric Crohn's Disease Activity Index (sPCDAI)(Week 6 (Induction period))
- Number of Participants with Endoscopic Response as Assessed by Simplified Endoscopic Score-Crohn's Disease (SES-CD)(Week 8 (Maintenance period))
- Number of Participants with Clinical Response as Assessed by sPCDAI(Week 6 (Induction period))
- Number of Participants with Clinical Remission at Week 44 (Maintenance Period) who are in Clinical Remission at Week 8 (Induction Period)(Week 44 (Maintenance Period))
- Number of Participants with Clinical Remission(Week 44 (Maintenance period))
- Number of Participants with Clinical Response(Week 44 (Maintenance period))
- Number of Participants with Endoscopic Response as Assessed by SES-CD(Week 44 (Maintenance period))
- Number of Participants with Corticosteroid-free Clinical Remission(Week 44 (Maintenance period))
- Global Outcome Measure: Percentage of Participants With Clinical Remission at Induction Week 6 as Assessed by Short Pediatric Crohn's Disease Activity Index (sPCDAI)(Induction Week 6 (Week I-6))
- Global Outcome Measure: Percentage of Participants With Clinical Response at Induction Week 8(Induction Week 8)
- Global and US-specific Outcome Measures: Percentage of Participants With Clinical Response at Induction Week 6 as Assessed by sPCDAI(Induction Week 6)
- Global Outcome Measure: Percentage of Participants With Endoscopic Response at Maintenance Week 8 as Assessed by Simplified Endoscopic Score-Crohn's Disease (SES-CD)(Maintenance Period Week 8 (Study Week 16))
- Global Outcome Measure: Percentage of Participants With Clinical Response at Maintenance Week 8(Maintenance Week 8 (Study Week 16))
- Global and US-specific Outcome Measures: Percentage of Participants With Endoscopic Response at Maintenance Week 44 as Assessed by SES-CD(Maintenance Week 44 (Study Week 52))
- US-specific Outcome Measure: Percentage of Participants With Clinical Response at Maintenance Week 44(Maintenance Week 44 (Study Week 52))
- US-specific Outcome Measure: Percentage of Participants With Corticosteroid-free Clinical Remission at Maintenance Week 44(Maintenance Period Week 44 (Study Week 52))
- Global Outcome Measure: Percentage of Participants With Clinical Remission at Maintenance Week 44 Who Had Clinical Remission at Induction Week 8(Maintenance Week 44 (Study Week 52))