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A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Ustekinumab in Participants With Takayasu Arteritis

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

14

Baseline characteristics included all 14 randomized participants who received at least 1 administration of study intervention. All 14 randomized participants were Asian (Japanese); 11 (78.6%) participants were female and 3 (21.4%) were male. The median (range) age of participants was 46.5 (31, 73) years in the placebo group and 37.5 (19, 49) years in the ustekinumab group. The median (range) weight of the participants was 52.0 (42.4, 84.6) kg in the placebo group and 76.05 (51.1, 100.9) kg in the ustekinumab group. The median (range) of body mass index (BMI) of participants was 21.40 (16.0, 28.9) kilograms per meter square (kg/m^2) in the placebo group and 25.73 (19.7, 37.7) kg/m^2 in the ustekinumab group.

Double-blind Period: A total of 14 participants were randomized in double-blind (DB) period of the study; 8 participants in the placebo group and 6 participants in the ustekinumab group. Out of 14 participants, 12 (85.7%) participants completed DB period; 6/8 (75.0%) participants from the placebo group and 6/6 (100.0%) participants from the ustekinumab group. Two (25.0%) participants from the placebo group discontinued study participation prematurely during DB period (due to protocol specified withdrawal criterion met in 1 participant and self withdrawal by another participant). All participants who discontinued study treatment due to early study termination by sponsor were included in the participants who completed DB period. All participants discontinued DB study intervention. The reasons for discontinuation of study treatment were disease relapse in 7 (50.0%) participants, (3/8 [37.5%] participants in the placebo and 4/6 [66.7%] participants in the ustekinumab group), study termination by sponsor in 5 (37.5%) participants (3/8 [37.5%] participants in the placebo and 2/6 [33.3%] participants in the ustekinumab group); adverse event (AE) and participant met protocol specified withdrawal criterion (in 1/8 [12.5%] participant in the placebo group each). Open Label Extension (OLE) Period: Due to the early study termination, all participants who entered into OLE period were participants who relapsed during DB period. A total of 7 participants entered into OLE period: 3 participants in the placebo-ustekinumab group and 4 participants in the ustekinumab-ustekinumab group. Out of 7 participants, 6 (85.7%) participants completed OLE period. One of 4 (25.0%) participants from the ustekinumab-ustekinumab group discontinued study participation prematurely due to self withdrawal during OLE period. All participants who discontinued study treatment due to early study termination by sponsor were included in the participants who completed OLE period. All participants discontinued OLE study intervention. The reasons for discontinuation of study treatment were study termination by the sponsor in 6 (85.7%) participants (3/3 [100.0%] participants in the placebo-ustekinumab group and 3/4 [75.0%] participants in the ustekinumab-ustekinumab group) and initiation of prohibited medication (1 [12.5%] participant) in the ustekinumab-ustekinumab group.

DB Period: Safety analysis included all participants who received at least 1 dose of study intervention through DB period. Through the end of DB period (up to 71.1 weeks), at least 1 treatment-emergent adverse event (TEAE) was reported in 6/8 (75.0%) participant in the placebo group and 5/6 (83.3%) participant in the ustekinumab group. Majority of TEAEs were mild or moderate in severity and a severe TEAE was reported in 1 participant in ustekinumab group. One of 8 (12.5%) participants in the placebo group and 1/6 (16.7%) participants in the ustekinumab group reported TEAE related to study intervention through the end of DB period. None of the participants reported TEAE leading to death. One of 8 (12.5%) participant in the placebo group and 1/6 (16.7%) participant in the ustekinumab group reported treatment emergent serious adverse events (TESAEs) through the end of DB period and none of them were considered related to study intervention. Adverse events (AEs) leading to discontinuation of study intervention were reported in 1/6 (12.5%) participant in the placebo group and none in the ustekinumab group. Infections were reported in 1/6 (12.5%) participant in the placebo group and 3/6 (50.0%) participants in the ustekinumab group. One (16.7%) participant in the ustekinumab and none in the placebo groups reported COVID-19 related TEAE through the end of DB period. There were no infusion and injection site reactions reported in the participants of both treatment groups through the end of DB period. OLE Period: Safety analysis included all participants who received at least 1 dose of study intervention through OLE period. Through the end of OLE period (up to 63.1 weeks), at least 1 TEAE was reported in 1/3 (33.3%) participants in the placebo-ustekinumab group and 2/4 (50.0%) participants in the ustekinumab-ustekinumab group. Majority of TEAEs were mild in severity and severe TEAEs were reported in 1 participant in the ustekinumab-ustekinumab group. None of the participants reported TEAE leading to death. One of 4 (25.0%) participants in the ustekinumab-ustekinumab and none in placebo-ustekinumab groups reported TESAE related to study intervention during OLE period. None of the participants reported AEs leading to discontinuation of study intervention. Infections were reported in 1/3 (33.3%) participant in the placebo-ustekinumab group and 2/4 (50.0%) participants in the ustekinumab-ustekinumab group. One (25.0%) participant in ustekinumab-ustekinumab and none in placebo-ustekinumab groups reported serious infections and COVID-19 related TEAE during OLE period. There were no infusion and injection site reactions reported in the participants of both treatment groups during OLE period.

Primary Efficacy Endpoint: Primary efficacy analysis was based on the full analysis set included all randomized participants (or directly enrolled into OLE period without randomization) who received at least 1 dose of study intervention. Time to Relapse Through the End of Double-blind (DB) Period: The median (95% CI) time to relapse (in weeks) was 12.64 (12.14, not estimable [NE]) in the placebo group compared to 11.14 (4.14, [NE]) in the ustekinumab group with hazard ratio (HR) (95% CI) of 1.86 (0.41, 8.47). The results could not be evaluated with sufficient sample size due to the early study termination. Secondary Safety Endpoints: Number of Participants with Treatment Emergent Adverse Events (TEAEs): DB period: Through the end of DB period, at least 1 TEAE was reported in 6/8 (75.0%) participant in the placebo group and 5/6 (83.3%) participant in the ustekinumab group. Majority of TEAEs were mild or moderate in severity and a severe TEAE was reported in 1 participant in ustekinumab group. OLE period: At least 1 TEAE was reported in 1/3 (33.3%) participants in the placebo-ustekinumab group and 2/4 (50.0%) participants in the ustekinumab-ustekinumab group. Number of Participants with TEAEs by System Organ Class (SOC) with a Frequency Threshold of 5 Percent (%) or More DB period: Overall, the most frequently (>=5% participants in either treatment group) reported AEs through the end of DB period were in the SOCs "Infections and infestations" and "Vascular disorders" (1/8 [12.5%] participant in the placebo group and 3/6 [50.0%] participants in the ustekinumab group for each SOC), followed by "General disorders and administration site conditions" (0 participant in the placebo group and 3/6 [50.0%] participants in the ustekinumab group), "Nervous system disorder" (0 participant in the placebo group and 2/6 [33.3%] participants in the ustekinumab group), "Eye disorders" (2/8 [25.0%] participants in the placebo group and 1/6 [16.7%] participant in the ustekinumab group), "Gastrointestinal disorders" (3/8 [37.5%] participant in the placebo group and 0 participant in the ustekinumab group), "Skin and subcutaneous tissue disorders" (2/8 [25.0%] participants in the placebo group and 0 participant in the ustekinumab group). OLE period: TEAEs reported with >=5% participants in either treatment group (placebo-ustekinumab, ustekinumab-ustekinumab) during OLE period were in the SOCs "Gastrointestinal disorders", "Injury, poisoning and procedural complications" and "Nervous system disorders" (1/3 [33.3%] participant in the placebo-ustekinumab group and 1/4 [25.0%] participant in the ustekinumab-ustekinumab group for each SOC), and "General disorders and administration site conditions", "Infections and infestations", "Investigations", "Respiratory, thoracic and mediastinal disorders" and "Vascular disorders" (0 participant in the placebo-ustekinumab group and 1/4 [25.0%] participant in the ustekinumab-ustekinumab group for each SOC). Number of Participants with Treatment-emergent Serious Adverse Events (SAEs) DB period: Through the end of DB period, TESAEs were reported in 1/8 (12.5%) participant in the placebo group) and 1/6 (16.7%) participant in the ustekinumab group. OLE period: During OLE period, TESAEs were reported in 1/4 (25.0%) participant in the ustekinumab-ustekinumab group (PT: Vascular graft infection) and none in the placebo-ustekinumab group during OLE period. Secondary Efficacy Endpoints: Time to Relapse of TAK by Kerr"s Criteria Through the End of DB Period The median (95% CI) time to relapse (in weeks) of TAK by Kerr"s Criteria Through the End of DB Period were 12.64 (12.14, NE) for placebo group and 11.14 (4.14, NE) for ustekinumab group, respectively. Time to Relapse of TAK Based on Clinical Symptoms Only Through the End of DB Period The median (95% CI) time to relapse (in weeks) of TAK based on clinical symptoms only through the end of DB period were 12.14 (2.14, NE) for placebo group and 4.14 (2.14, NE) for ustekinumab group, respectively. Time to Relapse of TAK in Each of the 5 Categories Through the End of DB Period: The median time to relapse (in weeks) of TAK based on objective systemic symptoms were 14 and NE (Not Estimable) for placebo and ustekinumab groups, respectively. The median time to relapse (in weeks) of TAK based on subjective systemic symptoms were 12.6 and 10 for placebo and ustekinumab groups, respectively. The median time to relapse (in weeks) of TAK based on elevated inflammation markers were 13.1 and 12.1 for placebo and ustekinumab groups, respectively. The median time to relapse (in weeks) of TAK based on vascular signs and symptoms were 12.1 and 7.1 for placebo and ustekinumab groups, respectively. There was no relapse of TAK based on ischemic symptoms. Percentage of Participants with Relapse in Each of the 5 Categories Through the End of DB Period: Percentage of participants of TAK for is defined as: objective systemic symptoms: 25.0% and 16.7% participant in placebo and ustekinumab groups respectively, subjective systemic symptoms: 37.5% and 50.0% in placebo and ustekinumab groups respectively, elevated inflammation markers: 50% each in placebo and ustekinumab groups, vascular signs and symptoms: 50% and 100% in placebo and ustekinumab groups respectively, or ischemic symptoms: 0% each in placebo and ustekinumab groups. Cumulative Oral Glucocorticoid (GC) Dose Through the End of DB Period: The mean (standard deviation) of GC dose through the end of DB period were 1043.6 (367.27) mg for placebo group and 1319.1 (697.67) mg for ustekinumab group, respectively. Change from Baseline in Oral GC Dose Through the End of DB Period: The change form baseline in oral GC dose through the end of DB period were -11.3 (3.73) milligrams (mg)/day mg/day in placebo group and -12.1 (6.25) mg/day in ustekinumab group, respectively. Number of Participants Achieving GC Dose of 5 milligrams (mg)/day or Less Through the End of DB Period: Number of participants achieving GC dose of 5 milligrams (mg)/day or less through the end of DB period were 3 in placebo group and 1 in ustekinumab group, respectively. Number of Participants with Change from Baseline in Imaging Evaluation Through the End of DB Period: No clear trend was observed in imaging assessments. Secondary Pharmacokinetic Endpoints: Change from Baseline in C-reactive Protein (CRP) Through the End of DB Period: No clear trend was observed for the effect of ustekinumab concentration on CRP in DB period. Change from Baseline in Erythrocyte Sedimentation Rate (ESR) Through the End of DB Period: No clear trend was observed for the effect of ustekinumab concentration on ESR in DB period. Serum Concentrations of Ustekinumab: Following a single intravenous (IV) administration of weight-range-based ustekinumab (260 mg {weight less than or equal [<=55 kg]; 390 mg [weight >55 kg to <=85 kg]; 520 mg [weight >85 kg]) approximating to 6 mg/kg at DB Week 0, the median serum ustekinumab concentration at 1-hour post-dose was 139.734 microgram per milliters (mcg/mL) (N=6). The median serum ustekinumab concentration at DB Week 8, prior to the first subcutaneous (SC) maintenance dose, was 8.745 mcg/mL (N=5). The serum ustekinumab concentration at DB Week 16 (before administration of the 2nd SC dose) was 3.811 mcg/mL (N=1). Number of Participants with Positive Anti-ustekinumab Antibodies: The overall incidence of treatment-induced antibodies to ustekinumab through DB period and through OLE period among the participants treated with ustekinumab who had evaluable serum samples was 0/6 participants (0%) and 0/9 participants (0%), respectively.

The target number of participants for this study was 50 (25 in each treatment group). However, the sponsor decided to terminate the study early and the study ended up with 14 enrolled participants: 8 in the placebo group and 6 in the ustekinumab group. The efficacy of ustekinumab cannot be concluded with this number of participants. No new safety signals were identified through the study.

May. 24, 2024

Yes

The data sharing policy of the Janssen Pharmaceutical Companies of Johnson & Johnson is available at www.janssen.com/clinicaltrials/ transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at yoda.yale.edu

https://jrct.mhlw.go.jp/latest-detail/jRCT2061210007

Nishikawa Kazuko

Janssen Pharmaceutical K.K.

3-5-2 Nishi-kanda, Chiyoda-ku, Tokyo

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Medical Information Center

Janssen Pharmaceutical K.K.

3-5-2 Nishi-kanda, Chiyoda-ku, Tokyo

+81-120-183-275

DL-JANJP-JCO_TL_TSG_EMP@its.jnj.com

Complete

Aug. 03, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

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

Both

Takayasu Arteritis

Ustekinumab
Participants will receive IV infusion and SC injection of ustekinumab.

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

Glucorticoid Taper Regimen
Glucocorticoid will be administered orally.

Time to Relapse Through the End of Double-blind (DB) Period
Up to occurrence of 35 events (Up to 24 months)
Time to relapse is defined as the assessment of 'signs of relapse present' as judged by the investigator for at least 2 of 5 categories: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms, or ischemic symptoms.

Number of Participants with Treatment Emergent Adverse Events (TEAEs)
Up to 3 years
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study treatment.

Number of Participants with TEAEs by System Organ Class (SOC) with a Frequency Threshold of 5 Percent (%) or More
Up to 3 years
An AE is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. TEAEs are defined as AEs with onset or worsening on or after date of first dose of study treatment.

Number of Participants with Treatment-emergent Serious Adverse Events (SAEs)
Up to 3 years
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 are defined as SAEs with onset or worsening on or after date of first dose of study treatment.

Time to Relapse of TAK by Kerr's Criteria Through the End of DB Period
Up to occurrence of 35 events (Up to 24 months)
Time to relapse is defined as the assessment of 'signs of relapse present' as judged by the investigator for at least 2 of 4 categories: systemic symptoms (objective or subjective), elevated inflammation markers, vascular signs, and symptoms and ischemic symptoms.

Time to Relapse Based on Clinical Symptoms Through the End of DB Period
Up to occurrence of 35 events (Up to 24 months)
Time to relapse based on clinical symptoms through the end of DB period will be reported. Participants who meet at least 1 category in the following 4 clinical categories will be considered as relapse per clinical symptom: 1) Objective systemic symptoms; 2) Subjective systemic symptoms; 3) Vascular signs and symptoms; 4) Ischemic symptoms.

Time to Relapse of TAK in Each of the 5 Categories Through the End of DB Period
Up to occurrence of 35 events (Up to 24 months)
Time to relapse is defined as the assessment of 'signs of relapse present' as judged by the investigator in each of the 5 categories: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms, or ischemic symptoms.

Percentage of Participants with Relapse in Each of the 5 Categories Through the End of DB Period
Up to occurrence of 35 events (Up to 24 months)
Percentage of participants with relapse in each of the 5 categories (objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms, or ischemic symptoms) through the end of DB period will be reported.

Cumulative Oral Glucocorticoid (GC) Dose Through the End of DB Period
Up to occurrence of 35 events (Up to 24 months)
Cumulative oral GC dose (prednisolone or equivalent) through the end of DB period will be reported.

Change from Baseline in Oral GC Dose Through the End of DB Period
Baseline; up to the end of DB period (Up to 24 months)
Change from baseline in oral GC dose (prednisolone or equivalent) through the end of DB period will be reported.

Number of Participants Achieving GC Dose of 5 milligrams (mg)/day or Less Through the End of DB Period
Up to 24 months
Number of participants achieving GC dose of 5 mg/day or less at the end of DB period will be reported.

Number of Participants with Change from Baseline in Imaging Evaluation Through the End of DB Period
Baseline, every 24 weeks from Week 0 and relapse confirmation visit (Up to 24 months)
Number of participants with change from baseline in imaging evaluation through the end of DB period will be reported. Vessel involvement such as stenosis, obstruction, and aneurysm; arterial wall thickness; and the presence of mural contrast enhancement and oedema will be assessed for imaging evaluation using magnetic resonance angiography (MRA).


Change from Baseline in C-reactive Protein (CRP) Through the End of DB Period
Baseline; up to 24 months
Change from baseline in CRP through the end of DB period will be reported.

Change from Baseline in Erythrocyte Sedimentation Rate (ESR) Through the End of DB Period
Baseline; up to 24 months
Change from baseline in ESR through the end of DB period will be reported.

Serum Concentrations of Ustekinumab
Up to end of study (Up to 3 years)
Serum concentrations of ustekinumab will be reported.

Number of Participants with Positive Anti-ustekinumab Antibodies
Up to end of study (Up to 3 years)
Number of participants with positive anti-ustekinumab antibodies will be reported.

+81-86-235-7534

May. 25, 2021

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