A Study of Ustekinumab in Participants With Takayasu Arteritis (TAK)

Phase 3TerminatedNCT04882072

Janssen Pharmaceutical K.K.14 enrolled

Overview

The purpose of this study is to evaluate the efficacy of ustekinumab compared to placebo, in combination with oral glucocorticoid (GC) taper regimen, in participants with relapsing Takayasu Arteritis (TAK).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

Conditions

Takayasu Arteritis

Interventions

UstekinumabDRUG

Participants will receive IV infusion and SC injection of ustekinumab.

PlaceboOTHER

Participants will receive IV infusion and SC injection of matching placebo.

Glucorticoid Taper RegimenDRUG

Glucocorticoid will be administered orally.

Eligibility

Sex: ALLMin age: 15 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Must have developed a relapse of Takayasu Arteritis (TAK) within 12 weeks prior to administration of study intervention and the relapse must have occurred at a dose of at least 7.5 milligrams (mg)/day (prednisolone or equivalent) * Must be receiving oral glucorticoid (GC) treatment of greater than or equal to (\>=)15 mg/day (prednisolone or equivalent), inclusive for the treatment of relapsing TAK and be on a stable dose for at least 2 weeks prior to the first administration of study intervention * If receiving an oral anti-platelet therapy (including but not limited to aspirin, clopidogrel, ticlopidine) or anti-coagulation therapy (including but not limited to warfarin) for treatment of TAK, the dose must have been stable for at least 2 weeks prior to first administration of the study intervention. In terms of warfarin, the dose should be controlled 1-5mg/day to maintain Prothrombin Time and International Normalized Ratio (PT-INR) target range between 2.0-3.0 (if participants are over 70 years old, PT-INR target range should be between 1.6-2.6) * Have no history of latent or active Tuberculosis (TB) prior to screening. An exception is made for participants who have a history of latent TB and are currently receiving treatment for latent TB, will initiate treatment for latent TB at least 3 weeks prior to the first administration of the study intervention, or have documentation of having completed appropriate treatment for latent TB within 3 years prior to the first administration of the study intervention. It is the responsibility of the investigator to verify the adequacy of previous antituberculous treatment and provide appropriate documentation * If receiving an oral anti-hypertensive therapy for treatment of TAK, the dose must have been stable for at least 2 weeks prior to first administration of the study intervention Exclusion Criteria: * Has currently any known severe or uncontrolled TAK complications (example, hypertension not responding to adequate treatment, aortic incompetence with cardiac insufficiency, progressing aortic aneurysm, coronary artery lesions with severe stenosis) * Has received immunosuppressant (s) (including but not limited to Methotrexate \[MTX\], Azathioprine \[AZA\], Mycophenolate Mofetil \[MMF\], oral Triamcinolone \[TAC\], oral Cyclosporine A) within 4 weeks of first study intervention * Has had a Bacille Calmette-guerin (BCG) vaccination within 12 months of screening * Any major illness/condition or evidence of an unstable clinical condition example, history of liver or renal insufficiency (estimated creatinine clearance below 60 milliliters/minute \[mL/min\]); significant (cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, psychiatric, or metabolic disturbances), disease of any organ system or active acute or chronic infection/infectious illness that, in the investigator's judgment, will substantially increase the risk to the participant if he or she participates in the study * Having a condition that is steroid dependent (example, steroid dependent asthma, chronic obstructive pulmonary disease, et cetera) that is not amenable to tapering oral GC

Locations (27)

Tokyo Medical and Dental University Hospital

Bunkyō City, Japan

Outcomes

Primary Outcomes

Time to Relapse (ToR) of Takayasu Arteritis (TAK) According to Protocol-defined Criteria Through the End of Double-blind Period

ToR:time from randomization to 1st relapse through end of double-blind period (EDBP) per protocol-defined criteria with 5 categories:systemic (objective):body temperature \>=38.0°C, weight loss \>2kg in 4 weeks, arthralgia, swelling \& tenderness =\>2 joints; systemic (subjective):malaise, myalgia, headache, dizziness/vertigo at \>= grade 2, high inflammation markers (C-reactive protein \>=1.0mg/dL, erythrocyte sedimentation rate \>=30mm/hr), vascular symptoms:renovascular hypertension: if normal BP \<120/80mmHg risen to \>=140/90mmHg, or if normal BP \>=120/80mmHg, diastolic BP risen by \>=20mmHg, new bruits/loss of pulse/difference in systolic BP between left and right by \>=10mmHg/tenderness/spontaneous pain in carotid artery/chest/back region, aortic valve incompetence; ischemic symptoms:abdominal pain, seizure, syncope, intermittent claudication, ischemic cardiac pain. Relapse:\>=2 categories met criteria.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Secondary Outcomes

Number of Participants With Treatment Emergent Adverse Events (TEAEs)

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study intervention. TEAEs were defined as AEs with onset or worsening on or after date of first dose of study intervention through the day of last dose.

Time frame: Double-blind period: Double-blind Week 0 up to end of double-blind treatment period (56.1 weeks); OLE period: OL Week 0 up to end of OLE treatment period (48.1 weeks)

Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)

SAE is any untoward medical occurrence that at any dose may 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. Treatment-emergent SAEs were defined as SAEs with onset or worsening on or after date of first dose of study intervention through the day of last dose.

Data from ClinicalTrials.gov

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Chiba University Hospital

Chiba, Japan

Kyushu University Hospital

Fukuoka, Japan

Hamamatsu University Hospital

Hamamatsu, Japan

Saitama Medical University Hospital

Iruma-gun, Japan

Kagawa University Hospital

Kita Gun, Japan

Kobe University Hospital

Kobe, Japan

Kyoto University Hospital

Kyoto, Japan

Matsuyama Red Cross Hospital

Matsuyama, Japan

Nagoya City University Hospital

Nagoya, Japan

...and 17 more locations

Time frame: Double-blind period: Double-blind Week 0 up to end of double-blind treatment period (56.1 weeks); OLE: OL Week 0 up to end of OLE treatment period (48.1 weeks)

Time to Relapse of TAK According to Kerr's Criteria Through the End of Double-blind Period

ToR was defined from the date of randomization to the judged date of relapse through the EDBP based on Kerr's definition: participants who met 2 or more categories in the following 4 categories were considered as relapse: systemic (objective):body temperature \>=38.0°C, weight loss \>2kg in 4 weeks, arthralgia, swelling \& tenderness =\>2 joints; systemic (subjective):malaise, myalgia, headache, dizziness/vertigo at \>= grade 2, high inflammation markers (C-reactive protein \>=1.0mg/dL, erythrocyte sedimentation rate \>=30mm/hr), vascular symptoms:renovascular hypertension: if normal BP \<120/80mmHg risen to \>=140/90mmHg, or if normal BP \>=120/80mmHg, diastolic BP risen by \>=20mmHg, new bruits/loss of pulse/difference in systolic BP between left and right by \>=10mmHg/tenderness/spontaneous pain in carotid artery/chest/back region, aortic valve incompetence; ischemic symptoms:abdominal pain, seizure, syncope, intermittent claudication, ischemic cardiac pain.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Time to Relapse of TAK Based on Clinical Symptoms Through the End of Double-blind Period

Time (in weeks) to relapse of TAK: time from randomization to the 1st relapse through the EDBP according to protocol-defined criteria with 5 categories: systemic (objective):body temperature \>=38.0°C, weight loss \>2kg in 4 weeks, arthralgia, swelling and tenderness =\>2 joints; systemic (subjective):malaise, myalgia, headache, dizziness/vertigo at \>= grade 2, high inflammation markers (C-reactive protein \>=1.0mg/dL, erythrocyte sedimentation rate \>=30mm/hr), vascular symptoms:renovascular hypertension: if normal BP \<120/80mmHg risen to \>=140/90mmHg, or if normal BP \>=120/80mmHg, diastolic BP risen by \>=20mmHg, new bruits/loss of pulse/difference in systolic BP between left and right by \>=10mmHg/tenderness/spontaneous pain in carotid artery/chest/back region, aortic valve incompetence; ischemic symptoms:abdominal pain, seizure, syncope, intermittent claudication, ischemic cardiac pain. Time to relapse was calculated by each category independently. Relapse:\>=2 categories met criteria.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Time to Relapse of TAK in Each of the 5 Categories (Within Protocol-defined Criteria) Through the End of Double-blind Period

Time to relapse of TAK: time from randomization date to the 1st relapse through the EDBP according to protocol-defined criteria with 5 categories: systemic (objective):body temperature \>=38.0°C, weight loss \>2kg in 4 weeks, arthralgia, swelling and tenderness =\>2 joints; systemic (subjective):malaise, myalgia, headache, dizziness/vertigo at \>= grade 2, high inflammation markers (C-reactive protein \>=1.0mg/dL, erythrocyte sedimentation rate \>=30mm/hr), vascular symptoms:renovascular hypertension: if normal BP \<120/80mmHg risen to \>=140/90mmHg, or if normal BP \>=120/80mmHg, diastolic BP risen by \>=20mmHg, new bruits/loss of pulse/difference in systolic BP between left and right by \>=10mmHg/tenderness/spontaneous pain in carotid artery/chest/back region, aortic valve incompetence; ischemic symptoms:abdominal pain, seizure, syncope, intermittent claudication, ischemic cardiac pain. Time to relapse was calculated by each category independently. Relapse:\>=2 categories met criteria.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Percentage of Participants With Relapse of TAK in Each of the 5 Categories (Within Protocol-defined Criteria) Through the End of Double-blind Period

Percentage of participants with time to relapse of TAK through the EDBP were reported. Protocol-defined criteria consisted of 5 categories: systemic (objective):body temperature \>=38.0°C, weight loss \>2kg in 4 weeks, arthralgia, swelling \& tenderness =\>2 joints; systemic (subjective):malaise, myalgia, headache, dizziness/vertigo at \>= grade 2, high inflammation markers (C-reactive protein \>=1.0mg/dL, erythrocyte sedimentation rate \>=30mm/hr), vascular symptoms:renovascular hypertension: if normal BP \<120/80mmHg risen to \>=140/90mmHg, or if normal BP \>=120/80mmHg, diastolic BP risen by \>=20mmHg, new bruits/loss of pulse/difference in systolic BP between left and right by \>=10mmHg/tenderness/spontaneous pain in carotid artery/chest/back region, aortic valve incompetence; ischemic symptoms: abdominal pain, seizure, syncope, intermittent claudication, ischemic cardiac pain.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Cumulative Oral Glucocorticoid (GC) Dose Through the End of Double-blind Period

Cumulative oral GC dose (prednisolone or equivalent) through the end of double-blind period were reported. If the participant had relapse, oral GC dose (prednisolone or equivalent) used from randomization date to last observed date prior to the date of relapse were included in the analysis and if the participant had no relapse then oral GC dose used from randomization to last observed date through the end of double-blind period were included in the analysis.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Change From Baseline in Oral GC Dose Through the End of Double-blind Period

Change from baseline in oral GC dose through the end of double-blind period were reported. Change from baseline was defined as the change between the GC dose at randomization and the last observed GC dose. If the participant had relapse, oral GC dose (prednisolone or equivalent) used from randomization date to last observed date prior to the date of relapse were included in the analysis and if the participant had no relapse then oral GC dose used from randomization to last observed date through the end of double-blind period were included in the analysis.

Time frame: Baseline (double-blind Week 0) up to end of double-blind period (up to 71.1 weeks)

Number of Participants Achieving GC Dose of 5 mg/Day or Less Through the End of Double-blind Period

Number of participants who achieved GC dose of 5 mg/day or less through the end of double-blind period were reported.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Change From Baseline in Imaging Evaluation of Vessel Involvement (Average Percentage of Dilation) at the End of Double-blind Period

Change from baseline in average percentage of dilation for abnormal vessel segments through the end of double-blind period was reported. Assessment was performed using computed tomography angiography (CTA) or magnetic resonance angiography (MRA). For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Time frame: Baseline (double-blind Week 0) and double-blind relapse (up to 14 weeks for Placebo arm; up to 48 weeks for ustekinumab arm)

Change From Baseline in Imaging Evaluation of Vessel Involvement (Average Percentage of Stenosis) Through the End of Double-blind Period

Change from baseline in average percentage of stenosis for abnormal vessel segments through the end of double-blind period was reported. Assessment was performed using CTA or MRA. For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Time frame: Baseline (double-blind Week 0), Week 24, Week 48, and double-blind relapse (up to 14 weeks for Placebo arm; up to 48 weeks for ustekinumab arm)

Change From Baseline in Imaging Evaluation of Average Arterial Wall Thickness Through the End of Double-blind Period

Change from baseline in average wall thickness for abnormal segments through the end of double-blind period was reported. Assessment was performed using CTA or MRA. For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Time frame: Baseline (double-blind Week 0), Week 24, Week 48, and double-blind relapse (up to 14 weeks for Placebo arm; up to 48 weeks for ustekinumab arm)

Imaging Evaluation: Number of Participants With Mural Contrast Enhancement Through the End of Double-blind Period

Number of participants with mural contrast enhancement through the end of double-blind period were reported. The mural contrast enhancement were assessed for imaging evaluation using CTA or MRA. For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Time frame: Baseline (double-blind Week 0), Week 24, Week 48, and double-blind relapse (up to 14 weeks for Placebo arm; up to 48 weeks for ustekinumab arm)

Change From Baseline in C-reactive Protein (CRP) Through the End of Double-blind Period

Change from baseline in CRP (as inflammatory marker) through the end of double-blind period were reported. For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Time frame: Baseline (double-blind Week 0), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, and double-blind relapse (up to 14 weeks for Placebo arm; up to 48 weeks for ustekinumab arm)

Change From Baseline in Erythrocyte Sedimentation Rate (ESR) Through the End of Double-blind Period

Change from baseline in ESR (as inflammatory marker) through the end of double-blind period were reported. For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Serum Concentrations of Ustekinumab in Participants Receiving Ustekinumab During Double-blind Phase

Serum concentrations of ustekinumab was reported during double-blind Phase. For a participant, the time point at which the 1st relapse developed or discontinuation from double-blind period was considered as the end of double-blind period.

Time frame: Pre-dose (double-blind Week 0), Post-dose: Week 0, Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, double-blind relapse (up to 48 weeks)

Serum Concentrations of Ustekinumab in Participants Receiving Ustekinumab During Open-label Extension Phase

Serum concentrations of ustekinumab was reported during OLE Phase.

Time frame: Pre-dose (OL Week 0), Post-dose: OL Week 0, OL Weeks 8, 16, 24, 32, 40, 48, 52, and 56

Number of Participants With Positive Anti-ustekinumab Antibodies Through End of Double-blind Period

Number of participants with positive anti-ustekinumab antibodies were reported.

Time frame: From double-blind Week 0 up to end of double-blind period (up to 71.1 weeks)

Number of Participants With Positive Anti-ustekinumab Antibodies Through End of OLE Period

Number of participants with positive anti-ustekinumab antibodies were reported.

Time frame: From OL Week 0 up to end of OLE period (up to 63.1 weeks)

Number of Participants With TEAEs by System Organ Class (SOC) With a Frequency Threshold of 5 Percent (%) or More

An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study intervention. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study intervention through the day of last dose. If same participant had more than one AE within the same SOC, that participant is counted only once in the below data table.

Time frame: Double-blind period: double-blind Week 0 up to end of double-blind treatment period (56.1 weeks); OLE period: OL Week 0 up to end of OLE treatment period (48.1 weeks)