A Multicenter, Randomized, Double-Blind, Placebo Controlled Induction Study to Evaluate the Efficacy and Safety of Risankizumab in Participants With Moderately to Severely Active Ulcerative Colitis
- Conditions
- Ulcerative Colitis (UC)
- Interventions
- Registration Number
- NCT03398148
- Lead Sponsor
- AbbVie
- Brief Summary
The objectives of Sub-Study 1 are to evaluate the efficacy, safety, and pharmacokinetics of risankizumab as induction treatment in subjects with moderately to severely active ulcerative colitis (UC), and to identify the appropriate induction dose of risankizumab for further evaluation in Sub-Study 2.
The objective of Sub-Study 2 is to evaluate the efficacy and safety of risankizumab compared to placebo in inducing clinical remission in subjects with moderately to severely active UC.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1558
- Male or female aged >=18 to <= 80 years at the Baseline Visit. Where locally permissible, subjects 16 to < 18 years of age who meet the definition of Tanner stage 5 for development at the Baseline Visit.
- Confirmed diagnosis of ulcerative colitis (UC) for at least 3 months prior to Baseline.
- Active UC as assessed by Adapted Mayo Score and Endoscopic Subscore.
- Demonstrated intolerance or inadequate response to conventional therapy and tofacitinib (not a biologic) and one or more biologic therapies.
- Females must be postmenopausal for more than 1 year or surgically sterile or practicing specific forms of birth control.
- Participant with a current diagnosis of Crohn's disease (CD), inflammatory bowel disease-unclassified (IBD-U) or a history of radiation colitis or ischemic colitis.
- Participant receiving prohibited medications and treatment.
- Extent of inflammatory disease limited to the rectum as assessed by screening endoscopy.
- Participant with currently known complications of UC (e.g., megacolon).
- No known active Coronavirus Disease - 2019 (COVID-19) infection.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Substudy 1, Induction Period 1: Double-blind Placebo IV placebo for risankizumab Participants randomized to receive placebo for risankizumab administered by intravenous (IV) infusion. Substudy 1, Induction Period 1: Double-blind Risankizumab 600mg IV risankizumab IV Participants randomized to receive risankizumab 600mg administered by intravenous (IV) infusion. Substudy 1, Induction Period 1: Double-blind Risankizumab 1200mg IV risankizumab IV Participants randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion. Substudy 1, Induction Period 1: Double-blind Risankizumab 1800mg IV risankizumab IV Participants randomized to receive risankizumab 1800mg administered by intravenous (IV) infusion. Substudy 1, Induction Period 1: Open-label Risankizumab 1800mg IV risankizumab IV Participants receive risankizumab 1800mg administered by intravenous (IV) infusion. Substudy 1, Induction Period 2: Double-blind Risankizumab 180mg SC risankizumab SC Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 180mg administered by subcutaneous (SC) injection in Induction 2. Substudy 1, Induction Period 2: Double-blind Risankizumab 360mg SC risankizumab SC Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 360mg administered by subcutaneous (SC) injection in Induction 2. Substudy 1, Induction Period 2: Double-blind Risankizumab 1800mg IV risankizumab IV Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 1800mg administered by intravenous (IV) infusion in Induction 2. Substudy 1, Induction Period 2: Double-blind Risankizumab 1800mg IV Pbo risankizumab IV Participants who received placebo with inadequate response in Induction 1 receive risankizumab 1800mg administered by intravenous (IV) infusion in Induction 2. Substudy 2, Induction Period 1: Double-blind Placebo IV placebo for risankizumab Participants randomized to receive placebo for risankizumab administered by intravenous (IV) infusion. Substudy 2, Induction Period 1: Double-blind Risankizumab 1200mg IV risankizumab IV Participants randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion. Substudy 2, Induction Period 2: Double-blind Risankizumab 180mg SC risankizumab SC Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 180mg administered by subcutaneous (SC) injection in Induction 2. Substudy 2, Induction Period 2: Double-blind Risankizumab 360mg SC risankizumab SC Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 360mg administered by subcutaneous (SC) injection in Induction 2. Substudy 2, Induction Period 2: Double-blind Risankizumab 1200mg IV risankizumab IV Participants who received risankizumab with inadequate response in Induction 1 randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion in Induction 2. Substudy 2, Induction Period 2: Double-blind Risankizumab 1200mg IV Pbo risankizumab IV Participants who received placebo with inadequate response in Induction 1 randomized to receive risankizumab 1200mg administered by intravenous (IV) infusion in Induction 2.
- Primary Outcome Measures
Name Time Method Sub-Study 1: Percentage of Participants Achieving Clinical Remission Per Adapted Mayo Score Week 12 The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores:
1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal)
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed)
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration)
The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease.
For Sub-Study 1, clinical remission was defined as SFS ≤ 1, and not greater than baseline, RBS of 0, and endoscopic subscore ≤ 1.Sub-Study 2: Percentage of Participants Achieving Clinical Remission Per Adapted Mayo Score Week 12 The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores:
1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal)
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed)
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration)
The overall Adapted Mayo score ranges from 0 to 9 where higher scores represent more severe disease.
For Sub-Study 2, clinical remission was defined as SFS ≤ 1, and not greater than baseline, RBS of 0, and endoscopic subscore ≤ 1. Evidence of friability during endoscopy in subjects with otherwise "mild" endoscopic activity will confer an endoscopic subscore of 2.
- Secondary Outcome Measures
Name Time Method Sub-Study 1: Percentage of Participants Achieving Endoscopic Improvement Week 12 Endoscopic improvement is defined as endoscopy subscore of 0 or 1.
Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).Sub-Study 1: Percentage of Participants Achieving Clinical Remission Per Full Mayo Score in Participants With a Full Mayo Score of 6 to 12 at Baseline Week 12 The Mayo score is a tool designed to measure disease activity for ulcerative colitis. The Full Mayo score (FMS) ranges from 0 (normal or inactive disease) to 12 (severe disease) and is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, endoscopy \[confirmed by a central reader\], and physician's global assessment), each of which ranges from 0 (normal) to 3 (severe disease). Negative changes indicate improvement.
Clinical remission per FMS is defined as Mayo Score ≤ 2 and no individual subscore \> 1.Sub-Study 1: Percentage of Participants Achieving Clinical Response Per Adapted Mayo Score Week 12 The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores:
1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal)
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed)
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration)
The overall Adapted Mayo Score ranges from 0 to 9 where higher scores represent more severe disease.
Clinical response per Adapted Mayo Score was defined as decrease from baseline in Adapted Mayo Score ≥ 2 points and ≥ 30%, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.Sub-Study 1: Percentage of Participants Achieving Clinical Response Per Partial Adapted Mayo Score Week 4 Clinical response per Partial Adapted Mayo Score (without endoscopy).
The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores:
1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal)
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed)
The overall Partial Mayo Score ranges from 0 to 6 with higher scores representing more severe disease.
Clinical response per Partial Mayo Score is defined as a decrease in Partial Adapted Mayo score \>= 1 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.Sub-Study 1: Percentage of Participants Achieving Endoscopic Remission Week 12 Endoscopic remission was defined as endoscopy subscore of 0.
Sub-Study 1: Percentage of Participants With Hospitalization Through Week 12 Participants with an event that results in admission to the hospital.
Sub-Study 1: Percentage of Participants Achieving Histologic Endoscopic Mucosal Remission (HEMR) Week 12 Mucosal healing defined as endoscopic and histologic remission.
Mucosal healing is defined as an endoscopic score of 0 and Geboes score \< 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration).
The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.Sub-Study 1: Change in Ulcerative Colitis Symptom Questionnaire (UC-SQ) Baseline Through Week 12 The US-SQ is a patient questionnaire to assess severity of Ulcerative Colitis (UC) related gastrointestinal symptoms (e.g., frequent bowel movements, abdominal pain, cramping) and non-gastrointestinal symptoms (e.g., joint pain and sleep difficulties).
It consists of 17 questions and each question is answered on a scale from can be answered on a scale from 1 (Not at all/ never) to 5 (Very much/Always) with overall symptom score range from 17 to 85. A lower score indicates lower UC severity.Sub-Study 2: Percentage of Participants Achieving No Abdominal Pain Week 12 Percentage of participants who reported no abdominal pain. Abdominal pain was assessed by participants in a subject diary completed once a day.
Sub-Study 1: Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Baseline Through Week 12 The IBDQ is used to assess the quality of life of patients with inflammatory bowel disease.
The IBDQ is a 32-item (ranges 1 - 7) self-report questionnaire for patients with IBD to evaluate the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), and emotional function (anger, depression, irritability).
The IBDQ total Score ranges from 32 to 224 with a higher score indicating better outcome.Sub-Study 1: Change From Baseline in Short Form-36 (SF-36) - Physical Component Baseline Through Week 12 The SF-36 (Version 2) is a self-administered, health-related survey that measures the impact of disease on overall quality of life during the past 4 weeks. SF-36 consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (mental \[MCS\] and physical \[PCS\]). MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain is scored by summing the individual items and transforming the scores into a 0 (poorest health) to 100 (best health) scale with higher scores indicating better health status or functioning.
Sub-Study 1: Change From Baseline in Short Form-36 (SF-36) - Mental Component Baseline through Week 12 The SF-36 (Version 2) is a self-administered, health-related survey that measures the impact of disease on overall quality of life during the past 4 weeks. SF-36 consists of 36 questions covering 8 health domains: physical functioning, bodily pain, role limitations due to physical problems and emotional problems, general health, mental health, social functioning, vitality, and 2 component scores (mental \[MCS\] and physical \[PCS\]). MCS consisted of social functioning, vitality, mental health, and role-emotional scales. PCS consisted of physical functioning, bodily pain, role-physical, and general health scales. Each domain is scored by summing the individual items and transforming the scores into a 0 (poorest health) to 100 (best health) scale with higher scores indicating better health status or functioning.
Sub-Study 1: Change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Baseline Through Week 12 The FACIT-Fatigue Scale is a validated self-administered 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a four-point Likert scale.
0 = not at all
1. = a little bit
2. = somewhat
3. = quite a bit
4. = very much
The FACIT Fatigue Scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better the quality of life. A positive change from baseline indicates improvement.Sub-Study 1: Percentage of Participants Undergoing Ulcerative Colitis (UC)-Related Surgeries Through Week 12 Participants who underwent surgery related to UC.
Sub-Study 2: Percentage of Participants Achieving Clinical Response Per Adapted Mayo Score Week 12 The Adapted Mayo Score is a composite score of UC disease activity based on the following 3 subscores:
1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal)
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed)
3. Endoscopic subscore, scored from 0 (normal or inactive disease) to 3 (severe disease, spontaneous bleeding, ulceration)
The overall Adapted Mayo Score ranges from 0 to 9 where higher scores represent more severe disease.
Clinical Response is defined as a decrease from baseline in the Adapted Mayo Score ≥ 2 points and ≥ 30% from baseline, and a decrease in RBS ≥ 1 or an absolute RBS ≤ 1).Sub-Study 2: Percentage of Participants Achieving Endoscopic Improvement Week 12 Endoscopic Improvement is defined as an endoscopic subscore of 0 or 1.
Endoscopies were assessed by a blinded central reader and scored according to the following scale: 0 = Normal or inactive disease; 1 = Mild disease (erythema, decreased vascular pattern); 2 = Moderate disease (marked erythema, lack of vascular pattern, any friability, erosions); 3 = Severe disease (spontaneous bleeding, ulceration).Sub-Study 2: Percentage of Participants Achieving Histologic Endoscopic Mucosal Improvement (HEMI) Week 12 Histologic-Endoscopic Mucosal Improvement is defined as an endoscopic subscore of 0 or 1 without evidence of friability and a Geboes score ≤ 3.1.
The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration).
The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers).
The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.Sub-Study 2: Percentage of Participants Achieving Endoscopic Remission Week 12 Endoscopic remission per endoscopy subscore.
Endoscopic Remission: endoscopic subscore = 0.Sub-Study 2: Percentage of Participants Achieving Clinical Response Per Partial Adapted Mayo Score at Week 4 Week 4 Clinical response per Partial Adapted Mayo Score (without endoscopy).
The Partial Mayo Score is a composite score of UC disease activity based on the following 2 subscores:
1. Stool frequency subscore (SFS), scored from 0 (normal number of stools) to 3 (5 or more stools more than normal)
2. Rectal bleeding subscore (RBS), scored from 0 (no blood seen) to 3 (blood alone passed)
The overall Partial Mayo Score ranges from 0 to 6 with higher scores representing more severe disease.
Clinical Response per Partial Mayo Score is defined as a decrease in Partial Adapted Mayo Score ≥ 1 points and ≥ 30% from Baseline, plus a decrease in RBS ≥ 1 or an absolute RBS ≤ 1.Sub-Study 2: Percentage of Participants Achieving No Bowel Urgency Week 12 Percentage of participants who reported no bowel urgency. Bowel urgency was assessed by participants in a subject diary completed once a day.
Sub-Study 2: Percentage of Participants Achieving Histologic Endoscopic Mucosal Remission (HEMR): Endoscopy Subscore of 0 and Geboes Score < 2.0) at Week 12 Week 12 Mucosal healing defined as endoscopic and histologic remission.
Mucosal healing is defined as an endoscopic score of 0 and Geboes score \< 2.0. The endoscopic subscore ranges from 0 (normal or inactive disease) to 3 (severe disease with spontaneous bleeding, ulceration).
The Geboes histologic index includes seven histological features (architectural change, chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in epithelium, crypt destruction and erosion or ulcers). The Geboes score has 6 grades, each with 3-5 subgrades: Grade 0, structural change only; Grade 1, chronic inflammation; Grade 2, lamina propria neutrophils and eosinophils; Grade 3, neutrophils in epithelium; Grade 4, crypt destruction; and Grade 5, erosions or ulceration.Sub-Study 2: Change in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Baseline to Week 12 The FACIT-Fatigue Scale is a validated self-administered 13-item tool that measures an individual's level of fatigue during their usual daily activities over the past 7 days. Each of the fatigue and impact of fatigue items are measured on a four-point Likert scale.
0 = not at all
1. = a little bit
2. = somewhat
3. = quite a bit
4. = very much
The FACIT Fatigue Scale is the sum of the individual 13 scores and ranges from 0 to 52 where higher scores indicate better the quality of life. A positive change from baseline indicates improvement.Sub-Study 2: Change in Inflammatory Bowel Disease Questionnaire (IBDQ) Total Score Baseline to Week 12 The IBDQ is used to assess the quality of life of patients with inflammatory bowel disease.
The IBDQ is a 32-item (ranges 1 - 7) self-report questionnaire for patients with IBD to evaluate the patient reported outcomes across 4 dimensions: bowel symptoms (loose stools, abdominal pain), systemic symptoms (fatigue, altered sleep pattern), social function (work attendance, need to cancel social events), and emotional function (anger, depression, irritability).
The IBDQ total Score ranges from 32 to 224 with a higher score indicating better outcome.Sub-Study 2: Occurrence of UC-related Hospitalizations Baseline Through Week 12 Participants with an UC-related event that results in admission to the hospital.
Sub-Study 2: Percentage of Participants Achieving No Nocturnal Bowel Movements Week 12 Percentage of participants who reported no nocturnal bowel movements.
Sub-Study 2: Percentage of Participants Achieving No Tenesmus Week 12 Percentage of participants who reported no tenesmus.
Sub-Study 2: Change in Number of Fecal Incontinence Episodes Per Week Baseline to Week 12 Change in number of fecal incontinence episodes per week.
Sub-Study 2: Change in Number of Days Per Week With Sleep Interrupted Due to UC Symptoms Baseline to Week 12 Change from baseline in number of days per week with sleep interrupted due to UC symptoms.
Trial Locations
- Locations (430)
Southern California Res. Ctr. /ID# 169660
🇺🇸Coronado, California, United States
Hoag Memorial Hosp Presbyterian /ID# 218348
🇺🇸Irvine, California, United States
UC San Diego Health System /ID# 160452
🇺🇸La Jolla, California, United States
United Medical Doctors /ID# 158528
🇺🇸Los Alamitos, California, United States
Gastrointestinal Biosciences Clinical Trials, LLC /ID# 200931
🇺🇸Los Angeles, California, United States
UCSF Center for Colitis and Crohn's Disease /ID# 201210
🇺🇸San Francisco, California, United States
Cedars-Sinai Medical Center-West Hollywood /ID# 163851
🇺🇸West Hollywood, California, United States
Peak Gastroenterology Associates, PC /ID# 165841
🇺🇸Colorado Springs, Colorado, United States
Rocky Mountain Pediatric Gastroenterology /ID# 207174
🇺🇸Lone Tree, Colorado, United States
Medical Research Center of CT /ID# 160311
🇺🇸Hamden, Connecticut, United States
Scroll for more (420 remaining)Southern California Res. Ctr. /ID# 169660🇺🇸Coronado, California, United States