A Study to Evaluate Efficacy and Safety of Ustekinumab Re-induction Therapy in Participants With Moderately to Severely Active Crohn's Disease

Crohn Disease Clinical Trial

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Official title:

A Phase 3b, Randomized, Double-blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Re-induction Therapy With Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03782376
• Other study ID #: CR108533
• Secondary ID: 2018-002629-51CN
• Status: Completed
• Phase: Phase 3
• Start date: December 20, 2018
• Est. completion date: January 10, 2023

Study information

• Verified date: February 2024
• Source: Janssen-Cilag Ltd.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary purpose of this study is to evaluate the efficacy and safety of a single intravenous (IV) re-induction dose of approximately 6 milligram per kilogram (mg/kg) ustekinumab in participants with secondary loss of response (LoR) to subcutaneous (SC) every 8 Weeks (q8w) 90 mg ustekinumab maintenance therapy.

Description:

This study compares the efficacy and safety of a single weight-tiered based IV re-induction dose of approximately 6 mg/kg ustekinumab versus continuing with regular SC q8w 90 mg ustekinumab administration. It consists of screening (5 weeks); treatment period (Week 0 to 24); and safety follow up visit (20 weeks after last dose). The primary hypothesis is that a single IV re-induction dose of ustekinumab is superior to continuing with regular SC q8w maintenance treatment as measured by clinical response after 16 weeks of treatment. Study assessments will include Crohn's disease activity index (CDAI), video ileocolonoscopy, patient-reported outcomes (PROs), laboratory evaluations, biomarkers, review of concomitant medications and adverse events (AEs), and evaluation of serum concentrations of study agent as well as development of antibodies to study agent. All participants will be randomly assigned to receive either ustekinumab IV re-induction or regular SC q8w 90 mg ustekinumab injection at baseline in a double dummy design. No participants will be treated with placebo only.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 215
• Est. completion date: January 10, 2023
• Est. primary completion date: August 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion criteria:

• A history of Crohn's disease or fistulizing Crohn's disease of at least 3 months' duration, with colitis, ileitis, or ileocolitis, confirmed at any time in the past by radiography, histology, and/or endoscopy

• Currently receiving subcutaneous 90 mg every 8 weeks (q8w) ustekinumab maintenance therapy and initially responded to ustekinumab induction therapy, administered according to the local label, followed by secondary loss of response (LoR) to ustekinumab. Secondary LoR to ustekinumab is defined as active disease at study baseline, proven by a Crohn's Disease Activity Index (CDAI) score of greater than or equal to (>=) 220 and <=450 with at least one of the following: Elevated C-reactive protein (CRP) (>3.0 milligram per liter [mg/L]); and/or elevated Fecal calprotectin (fCal) >250 milligram per kilogram [mg/kg]); and/or endoscopy (performed less than or equal to (<=) 3 months before baseline) with evidence of active Crohn's disease, (defined as one or more ulcerations in the ileum and/or colon)

• Participants receiving either oral 5-aminosalicylic acid (5-ASA) compounds, oral corticosteroids (for example {e.g.}, prednisone, budesonide) at a prednisone-equivalent dose of <=40 mg/day or <=9 mg/day of budesonide, antibiotics used as the primary treatment of Crohn's disease, or conventional immunomodulators (i.e., azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate [MTX]) are permitted providing the doses indicated are stable before baseline or have been discontinued before baseline within the protocol defined durations

Exclusion Criteria:

• Complications of Crohn's disease, such as symptomatic strictures or stenoses, short gut syndrome, or any other manifestation that might be anticipated to require surgery, could preclude the use of the CDAI to assess response to therapy, or would possibly confound the ability to assess the effect of treatment with ustekinumab

• 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 before baseline (or 8 weeks before baseline for intra-abdominal abscesses) provided there is no anticipated need for any further surgery. Participants with active fistulas may be included if there is no anticipation of a need for surgery and there are currently no abscesses identified

• Any kind of bowel resection within 6 months or any other intra-abdominal surgery within 3 months before baseline

• A draining (i.e., functioning) stoma or ostomy

• Received ustekinumab intravenous re-induction after the initial weight-tiered-based IV induction dose of ustekinumab

• Any known history of shortened frequency of SC dose administration (<q8w) for a secondary loss of response where the participant did not, in the opinion of the treating physician, benefit from the dose interval shortening

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Drug:
• Ustekinumab approximately 6 mg/kg (IV)
Participants will receive ustekinumab approximately 6mg/kg intravenously at Week 0.
• Placebo (SC)
Participants will receive SC injection of placebo at Week 0.
• Placebo (IV)
Participants will receive IV infusion of placebo at Week 0.
• Ustekinumab 90 mg (SC) Group 1
Participants will receive SC injection of ustekinumab 90 mg at Weeks 8 and 16.
• Ustekinumab 90 mg (SC) Group 2
Participants will receive SC injection of ustekinumab 90 mg at Weeks 0, 8 and 16.

Locations

Country	Name	City	State
Austria	Krankenhaus der Barmherzigen Brüder	Wien
Austria	Medizinische Universität Wien	Wien
Czechia	Hepato-gastroenterologie HK, s.r.o.	Hradec Kralove
Czechia	ISCARE a.s.	Praha 9
France	Hopital Beaujon	Clichy
France	CHRU de Lille - Hopital Claude Huriez	Lille
France	CHRU Montpellier - Hopital Saint-Eloi	Montpellier
France	CHU Hopital Saint Antoine	Paris cedex 12
France	Hospices Civils de Lyon HCL	Pierre Bénite
France	CHRU Hopital de Pontchaillou	Rennes
France	CHU de Nancy_ Hopital Brabois	Vandoeuvre-les-Nancy
Germany	Klinikum Augsburg	Augsburg
Germany	Charite - Universitaetsmedizin Berlin (CCM)	Berlin
Germany	GASTRO-Studien	Berlin
Germany	Medizinisches Versorgungszentrum (MVZ) Dachau	Dachau
Germany	University Hospital Dresden	Dresden
Germany	Agaplesion Frankfurter Diakonie Kliniken GmbH, Markus Krankenhaus	Frankfurt
Germany	Universitatsklinikum Frankfurt/ Medizinische Klinik 1	Frankfurt
Germany	Universitatsklinikum Freiburg	Freiburg
Germany	Städtisches Krankenhaus Martha-Maria Halle-Dölau gGmbH	Halle
Germany	Hamburgisches Forschungsinstitut fuer CED, HaFCED e.K.	Hamburg
Germany	Gastroenterologie Opernstrasse	Kassel
Germany	Universitatsklinikum Schleswig Holstein Kiel	Kiel
Germany	Staedtisches Klinikum Lueneburg	Lueneburg
Germany	Universitätsklinikum Otto-von-Guericke-Universität Magdeburg	Magdeburg
Germany	Medizinische Fakultät Mannheim der Universität Heidelberg	Mannheim
Germany	Gastroenterologische Gemeinschaftspraxis Minden	Minden
Germany	Klinikum der Universitaet Muenchen	Muenchen
Germany	Praxis Dr. med. Ulf Helwig	Oldenburg
Germany	Zentrum für Gastroenterologie Saar MVZ GmbH	Saarbrücken
Germany	Universitaetsklinik Tuebingen	Tübingen
Germany	Universitaetsklinikum Ulm, Klinik fuer Innere Medizin II	Ulm
Italy	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico	Milano
Italy	Ospedale Villa Sofia-Cervello	Palermo
Italy	Azienda Ospedaliera G.Salvini Ospedale di Rho	RHO
Italy	Fondazione Policlinico Gemelli Università Cattolica	Roma
Italy	Istituto Clinico Humanitas	Rozzano
Italy	AO Ordine Mauriziano	Torino
Korea, Republic of	Inje University Haeundae Paik Hospital	Busan
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	KyungHee University Hospital	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System	Seoul
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	Leiden University Medical Center	Leiden
Netherlands	Maastricht Universitair Medisch Centrum	Maastricht
Netherlands	Radboudumc	Nijmegen
Netherlands	Erasmus MC	Rotterdam
Netherlands	Sint Franciscus Gasthuis	Rotterdam
Russian Federation	Irkutsk State Medical Academy of Postgraduate Education	Irkutsk
Russian Federation	Olla-Med, Llc	Moscow
Russian Federation	City Clinical Hospital #31	St. Petersburg
Russian Federation	GBUZ Respublican Clinical Hospital n.a. GG Kuvatova	Ufa
Spain	Hosp. Univ. Fundacion Alcorcon	Alcorcón
Spain	Hosp. Arquitecto Marcide	Ferrol
Spain	Hosp. Gral. Univ. Gregorio Maranon	Madrid
Spain	Hosp. Univ. La Paz	Madrid
Spain	Hosp. Virgen de La Victoria	Málaga
Spain	Hosp. Univ. Virgen de La Arrixaca	Murcia
Spain	Hosp. de Navarra	Pamplona
Spain	Hosp. Montecelo	Pontevedra
Spain	Corporacio Sanitari Parc Tauli	Sabadell
Spain	Hosp. Clinico Univ. de Salamanca	Salamanca
Spain	Hosp. Univ. Marques de Valdecilla	Santander
Spain	Hosp. Clinico Univ. de Valencia	Valencia
Spain	Hosp. Alvaro Cunqueiro	Vigo
Spain	Hosp. Clinico Univ. Lozano Blesa	Zaragoza
Spain	Hosp. Univ. Miguel Servet	Zaragoza
Sweden	Gastromottagningen	Malmö
Sweden	Gastromottagningen	Stockholm
United Kingdom	Pennine Acute Hospitals-Fairfield General Hospital	Bury
United Kingdom	Gloucestershire Hospitals NHS Foundation Trust - Cheltenham	Cheltenham
United Kingdom	Royal Devon & Exeter Hospital	Exeter
United Kingdom	King's College Hospital NHS Foundation Trust	London
United Kingdom	St George's Hospital	London
United Kingdom	Southampton University Hospitals NHS Trust	Southampton
United States	Atlanta Gastroenterology Associates, (AGA) LLC - Emory Saint Joseph's	Atlanta	Georgia
United States	Emory University	Atlanta	Georgia
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Texas Digestive Disease Consultants	Cedar Park	Texas
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Chevy Chase Clinical Research	Chevy Chase	Maryland
United States	Peak Gastroenterology Associates	Colorado Springs	Colorado
United States	Florida Research Network, LLC	Gainesville	Florida
United States	Ohio State University Hospital	Hilliard	Ohio
United States	Baylor College of Medicine	Houston	Texas
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	University of California, San Diego	La Jolla	California
United States	University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Mount Sinai School of Medicine	New York	New York
United States	Oklahoma Digestive Disease Specialists	Oklahoma City	Oklahoma
United States	Advent Health	Orlando	Florida
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Gastroenterology Research of America, LLC	San Antonio	Texas
United States	University of Washington	Seattle	Washington
United States	Virginia Mason Medical Center	Seattle	Washington
United States	Atlanta Gastroenterology Specialists	Suwanee	Georgia
United States	Washington Gastroenterology, PLLC	Tacoma	Washington
United States	Florida Hospital Tampa	Tampa	Florida
United States	Tyler Research Institute, LLC	Tyler	Texas
United States	Northshore Gastroenterology Research, LLC	Westlake	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Janssen-Cilag Ltd.

Countries where clinical trial is conducted

United States,  Austria,  Czechia,  France,  Germany,  Italy,  Korea, Republic of,  Netherlands,  Russian Federation,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Clinical Response at Week 16	Clinical response was defined as greater than or equal to (>=) 100-point reduction from baseline in Crohn's disease activity index (CDAI) score or a CDAI score < 150 points. CDAI is validated multi-item measure of severity of illness derived as weighted sum of 8 different Crohn's disease (CD)-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score.	Week 16
Secondary	Percentage of Participants With Clinical Remission at Week 16	Percentage of participants with clinical remission at Week 16 were reported. Clinical remission was defined as CDAI score of <150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score.	Week 16
Secondary	Percentage of Participants With Clinical Response at Week 8	Clinical response was defined as a >=100-point reduction from the baseline in CDAI score or a CDAI score <150 point. The CDAI is a validated multi-item measure of severity of illness derived as a weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by the participant on a diary card. In general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score.	Week 8
Secondary	Percentage of Participants With Clinical Remission at Week 8	Percentage of participants with clinical remission at Week 8 were reported. Clinical remission was defined as CDAI score of <150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score.	Week 8
Secondary	Percentage of Participants With Normalization of C-reactive Protein (CRP) and/or Normalization of Fecal Calprotectin (fCal) Concentration at Week 16	Percentage of participants with normalization at Week 16, among participants with elevated CRP and/or fCal at baseline were reported. Participants were considered to be normalized if at least one biomarker (fCal or CRP) was normalized. Normalized CRP=CRP value less than or equal to (<=) 3 milligrams per liter(mg/L). Normalized fCal concentrations was defined as <=250 micrograms per gram(mcg/g). When either CRP or FCal value was abnormal at baseline and value of same parameter normalizes at designated analysis timepoint, participants were considered to be normalized at designated analysis timepoint. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint are considered not to be normalized. Participants who had insufficient data at designated analysis timepoint had their last value carried forward.	Week 16
Secondary	Percentage of Participants With Clinical Remission at Week 24	Percentage of participants with clinical remission at Week 24 were reported. Clinical remission was defined as CDAI score of <150 points. CDAI is a validated multi-item measure of severity of illness derived as weighted sum of 8 different CD-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates and general well-being). The last 4 variables were scored over 7 days by participant on diary card. In general, CDAI score ranges from 0 to approximately 600; higher score=higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical remission, regardless of their CDAI score.	Week 24
Secondary	Percentage of Participants With Clinical Response at Week 24	Clinical response was defined as a >=100-point reduction from the baseline in CDAI score or a CDAI score <150 point. The CDAI is a validated multi-item measure of severity of illness derived as a weighted sum of 8 different Crohn's disease-related variables (extra-intestinal manifestations, abdominal mass, weight, hematocrit, total number of liquid stools, abdominal pain/cramping, use of antidiarrheal drug(s) and/or opiates, and general well-being). The last 4 variables were scored over 7 days by the participant on a diary card. In general, CDAI score ranges from 0 to approximately 600; higher score indicates higher disease activities. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint were considered not to be in clinical response, regardless of their CDAI score.	Week 24
Secondary	Percentage of Participants With Normalization of C-reactive Protein (CRP) and/or Normalization of Fecal Calprotectin (fCal) Concentration at Week 24	Percentage of participants with normalization at Week 24, among participants with elevated CRP and/or fCal at baseline were reported. Participants were considered to be normalized if at least one biomarker (fCal or CRP) was normalized. Normalized CRP=CRP value less than or equal to (<=) 3 milligrams per liter(mg/L). Normalized fCal concentrations was defined as <=250 micrograms per gram(mcg/g). When either CRP or FCal value was abnormal at baseline and value of same parameter normalizes at designated analysis timepoint, participants were considered to be normalized at designated analysis timepoint. Participants who had prohibited CD-related surgery, prohibited concomitant medication changes, or discontinued study agent due to lack of efficacy or adverse event indicated to be of worsening CD prior to designated analysis timepoint are considered not to be normalized. Participants who had insufficient data at designated analysis timepoint had their last value carried forward.	Week 24
Secondary	Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)	An adverse event was any untoward medical occurrence in a clinical study participant administered a medicinal (investigational or non-investigational) product. An adverse event does not necessarily have a causal relationship with the treatment. TEAEs were adverse events with onset during the intervention phase or that were a consequence of a pre-existing condition that had worsened since baseline. Any AE occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent. In this outcome measure, TEAEs including all AEs irrespective of being serious or non-serious AE are reported.	From baseline (Week 0) up to Week 36
Secondary	Percentage of Participants With Treatment-emergent Serious Adverse Events (TESAEs)	A serious adverse event (SAE) was an adverse event 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; congenital anomaly; a suspected transmission of any infectious agent via a medicinal product; medically important. TESAEs were adverse events with onset during the intervention phase or that are a consequence of a pre-existing condition that had worsened since baseline. Any AE occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent.	From baseline (Week 0) up to Week 36
Secondary	Percentage of Participants With Treatment-emergent Infections	Percentage of participants with treatment-emergent infections were reported. Any infection occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent.	From baseline (Week 0) up to Week 36
Secondary	Percentage of Participants With Treatment-emergent Serious Infections	Percentage of participants with treatment-emergent serious infections was reported. Any infection occurring at or after the initial administration of study agent through the end of the trial was considered to be treatment emergent.	From baseline (Week 0) up to Week 36
Secondary	Change From Baseline in Clinical Laboratory Values for Hematology (Hemoglobin) and Chemistry (Albumin, Total Protein)	Change from baseline in clinical laboratory values for hematology (hemoglobin) and chemistry (albumin, total protein) was reported.	Baseline, Weeks 8, 16, 24
Secondary	Change From Baseline in Clinical Laboratory Values for Hematology (Hematocrit)	Change from baseline in clinical laboratory values for hematology (hematocrit) was reported.	Baseline, Weeks 8, 16, 24
Secondary	Change From Baseline in Clinical Laboratory Values for Hematology (Total White Blood Cell [WBC], Neutrophils, Absolute Lymphocyte, Eosinophils, Platelets)	Change from baseline in clinical laboratory values for hematology (total WBC, neutrophils, absolute lymphocyte, eosinophils, platelets) was reported.	Baseline, Weeks 8, 16, 24
Secondary	Change From Baseline in Clinical Laboratory Values for Chemistry (Alkaline Phosphatase, Alanine Transaminase [ALT], Aspartate Transaminase [AST])	Change from baseline in clinical laboratory values for chemistry (alkaline, ALT, AST) was reported.	Baseline, Weeks 8, 16, 24
Secondary	Change From Baseline in Clinical Laboratory Values for Chemistry (Total Bilirubin, Direct Bilirubin, Creatinine)	Change from baseline in clinical laboratory values for chemistry (total bilirubin, direct bilirubin, creatinine) was reported.	Baseline, Weeks 8, 16, 24
Secondary	Change From Baseline in Clinical Laboratory Values for Chemistry (Sodium, Potassium, Chloride, Blood Urea Nitrogen [BUN]/Urea, Calcium, Phosphate)	Change from baseline in clinical laboratory values for chemistry (sodium, potassium, chloride, BUN/urea, calcium, phosphate) was reported.	Baseline, Weeks 8, 16, 24