A Phase 2a, Efficacy and Safety Study of Ustekinumab in Systemic Lupus Erythematosus

• ClinicalTrials.gov Identifier: NCT02349061
• Recruitment Status: Completed
• First Posted: January 28, 2015
• Results First Posted: June 12, 2018
• Last Update Posted: March 24, 2020
• Sponsor: Janssen Research & Development, LLC
• Information provided by (Responsible Party): Janssen Research & Development, LLC

Study Description

Brief Summary:

The purpose of this study is to evaluate the efficacy of ustekinumab as measured by a reduction in disease activity for subjects with active Active Systemic Lupus Erythematosus (SLE - chronic disorder of connective tissue in which there can be skin rash, arthritis, kidney problems, and anemia, among other problems).

Condition or disease	Intervention/treatment	Phase
Lupus Erythematosus, Systemic	Drug: Ustekinumab IV; Drug: Placebo Infusion; Drug: Placebo SC; Drug: Ustekinumab SC; Other: Concomitant Medication	Phase 2

Detailed Description:

A multicenter (more than one medical research center involved in study), randomized (study drug assigned by chance), double-blind (neither the Investigator nor the participant know about the study drug), placebo-controlled, proof-of-concept study of ustekinumab in participants with active systemic lupus erythematosus. Participants will be screened to achieve all inclusion criteria and none exclusion criteria and will then receive either ustekinumab or placebo along with concomitant background medicine. Participants will be primarily assessed for response using the Systemic Lupus Erythematosus Response Index 2000 (SRI-4). Participants' safety will be assessed throughout the study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Proof-of-Concept Study of Ustekinumab in Subjects With Active Systemic Lupus Erythematosus
• Actual Study Start Date: October 15, 2015
• Actual Primary Completion Date: May 15, 2017
• Actual Study Completion Date: March 13, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ustekinumab plus Concomitant Medication; Participants will receive weight-range based dosing of approximately 6 mg/kg of ustekinumab intravenously at Week 0 followed by ustekinumab 90 mg subcutaneously (SC) every 8 weeks (q8w) up to Week 40. Participants who meet the study extension inclusion criteria will continue to receive ustekinumab 90 mg SC q8w starting at Week 48 or 56 through Week 104. Participants will continue stable concomitant treatment through Week 48, as well as through the study extension although tapering of corticosteroids is encouraged beyond Week 48. Participants who complete or discontinue study treatment will be evaluated for 16 additional Weeks of safety follow-up.	Drug: Ustekinumab IV; Weight-range based dosing of approximately 6 mg/kg of ustekinumab intravenously at Week 0.; Other Name: STELARA; Drug: Ustekinumab SC; Ustekinumab 90 mg subcutaneously every 8 weeks up to Week 40 and up to Week 104 in study extension (for eligible participants); Other: Concomitant Medication; Concomitant treatment (mycophenolate, azathioprine/6-mercaptopurine, methotrexate, hydroxychloroquine and/or chloroquine, oral corticosteroids, NSAIDs, antihypertensive medications, and topical medications) through Week 48, as well as through the study extension although tapering of corticosteroids is encouraged beyond Week 48.
Experimental: Placebo followed by Ustekinumab plus Concomitant Medication; Participants will receive placebo intravenously at Week 0 followed by placebo subcutaneously at Weeks 8 and 16. At week 24 participants will receive ustekinumab SC q8w up to Week 40. Participants who meet the study extension inclusion criteria will continue to receive ustekinumab 90 mg SC q8w starting at Week 48 or 56 through Week 104. Participants will continue stable concomitant treatment through Week 48, as well as through the study extension although tapering of corticosteroids is encouraged beyond Week 48. Participants who complete or discontinue study treatment will be evaluated for 16 additional Weeks of safety follow-up.	Drug: Placebo Infusion; Placebo intravenously at Week 0.; Drug: Placebo SC; Placebo subcutaneously at Weeks 8 and 16.; Drug: Ustekinumab SC; Ustekinumab 90 mg subcutaneously every 8 weeks up to Week 40 and up to Week 104 in study extension (for eligible participants); Other: Concomitant Medication; Concomitant treatment (mycophenolate, azathioprine/6-mercaptopurine, methotrexate, hydroxychloroquine and/or chloroquine, oral corticosteroids, NSAIDs, antihypertensive medications, and topical medications) through Week 48, as well as through the study extension although tapering of corticosteroids is encouraged beyond Week 48.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With a Systemic Lupus Erythematosus Responder Index (SRI-4) Composite Response (CR) at Week 24 [ Time Frame: Week 24 ]
   SRI-4 response was defined as greater than or equal to 4-point reduction in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) total score, no new British Isles Lupus Assessment Group (BILAG) A and no more than 1 new BILAG B domain score and no worsening (less than 10 percent increase) from baseline in Physician's Global Assessment of Disease Activity (PGA). Composite response is defined as SRI-4 response in participants who do not meet treatment failure criteria. SLEDAI-2K assessment consists of 24 items with total score of 0 to 105, with higher scores representing increased disease activity. BILAG Index: assessing clinical signs, symptoms, or laboratory parameters related to SLE, divided into 9 organ systems. For each organ system: A=severe disease, B=moderate disease, C=mild stable disease, D=inactive, but previously active, E=inactive and never affected. The PGA assess disease activity on a visual analogue scale = from very well (0)-very poor (10).

Secondary Outcome Measures :

1. Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) Score at Week 24 [ Time Frame: Baseline, Week 24 ]
   The SLEDAI-2K is an established, validated SLE activity index. It is based on the presence of 24 features in 9 organ systems and measures disease activity in SLE patients in the previous 30 days. It is weighted according to the feature. Features are scored by the assessing physician if present within the last 30 days with more severe features having higher scores, and then simply added to determine the total SLEDAI 2K score, which ranges from 0 to 105, with higher scores representing increased disease activity.
2. Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24 [ Time Frame: Baseline, Week 24 ]
   PGA was recorded on a visual analogue scale (VAS; 0.0 to 10.0 centimeter [cm]). The scale for the physician's assessment ranges for 'no lupus activity' (0.0) to 'extremely active lupus' (10.0).
3. Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24 [ Time Frame: Week 24 ]
   BICLA response defined as participants meeting following criteria: 1. BILAG improvement (all BILAG A scores at baseline improved to either B, C or D and all BILAG B scores at baseline improved to C or D and no worsening in disease activity defined as no new BILAG A scores and <= 1 new BILAG B score) and 2. no worsening of total SLEDAI-2K from baseline 3. < 1 cm increase in PGA and 4. no treatment failure criteria met. BILAG: assesses disease extent, severity (range: A [severe] to E [no disease]). SLEDAI-2K: assesses improvement in disease activity (range: 0 to 105; higher score = higher severity). PGA: assesses worsening in participant's general health status (0.0= 'no lupus activity' to 10.0 = 'extremely active lupus').
4. Change From Baseline in Number of Joints With Pain and Signs of Inflammation at Week 24 [ Time Frame: Baseline, Week 24 ]
   Change from baseline in number of joints (active joint) with pain and signs of inflammation (tenderness, swelling or effusion) for participants with at least 2 affected joints at baseline were reported. An active joint is defined as a joint with pain and signs of inflammation (e.g., tenderness, swelling or effusion).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Subjects must have documented medical history to meet SLICC classification criteria for SLE for a minimum of 3 months prior to first dose
• At least 1 well-documented (subject file, referring physician letter, or laboratory result), unequivocally positive, documented test for autoantibodies in medical history including either of the following: ANA, and/or anti-dsDNA antibodies, and/or anti-Smith antibodies
• At least 1 unequivocally positive autoantibody test including ANA and/or anti-dsDNA antibodies and/or anti-Smith antibodies detected during screening
• At least 1 BILAG A and/or 2 BILAG B domain scores observed during screening prior to first administration of study agent
• Demonstrate active disease based on SLEDAI-2K score greater than or equal to (>=) 6 observed during screening and assessed approximately 2 to 6 weeks prior to randomization. Must also have SLEDAI-2K score >= 4 for clinical features (ie, SLEDAI excluding laboratory results) at Week 0 prior to the first administration of study agent

Exclusion Criteria:

• Have other inflammatory diseases that might confound the evaluations of efficacy, including but not limited to rheumatoid arthritis (RA), psoriatic arthritis (PsA), RA/lupus overlap, psoriasis or active Lyme disease
• Are pregnant, nursing, or planning a pregnancy or fathering a child while enrolled in the study or within 4 months after receiving the last administration of study agent
• Have received systemic or topical cream/ointment preparations of cyclosporine A or other systemic immunomodulatory agents other than those described in inclusion criteria within the past 3 months prior to first administration of study agent
• Have received a single B cell targeting agent within 3 months prior to first study agent administration; or received more than 1 previous B cell targeting therapy including belimumab or epratuzamab within 6 months prior to first administration of the study agent; or received B cell depleting therapy (eg, rituximab) within 12 months prior to first administration of the study agent or have evidence of continued B-cell depletion following such therapy
• Have ever received ustekinumab
• Participant has a history of malignancy within 5 years before screening (exceptions are squamous and basal cell carcinomas of the skin that has been treated with no evidence of recurrence for at least 3 months before the first study agent administration and carcinoma in situ of the cervix that has been surgically cured)

Contacts and Locations

Locations

United States, Alabama

Huntsville, Alabama, United States

United States, California

Beverly Hills, California, United States

United States, Florida

Tampa, Florida, United States

United States, Michigan

Lansing, Michigan, United States

United States, New York

Manhasset, New York, United States

New York, New York, United States

Syracuse, New York, United States

United States, Oklahoma

Tulsa, Oklahoma, United States

United States, Pennsylvania

Duncansville, Pennsylvania, United States

Philadelphia, Pennsylvania, United States

United States, South Carolina

Charleston, South Carolina, United States

United States, Tennessee

Jackson, Tennessee, United States

Argentina

Buenos Aires, Argentina

Ciudad De San Miguel De Tucuman, Argentina

San Juan, Argentina

Australia

Adelaide, Australia

Camberwell, Australia

Heidelberg, Australia

Liverpool, Australia

Nedlands, Australia

Germany

Berlin, Germany

Frankfurt, Germany

Koeln, Germany

Hungary

Budapest, Hungary

Debrecen, Hungary

Szeged, Hungary

Zalaegerszeg, Hungary

Mexico

Chihuahua, Mexico

Guadalajara, Mexico

Leon, Mexico

Mexico, Mexico

Poland

Bydgoszcz, Poland

Poznan, Poland

Szczecin, Poland

Wroclaw, Poland

Spain

Barcelona, Spain

Madrid, Spain

Málaga, Spain

Santiago de Compostela, Spain

Sevilla, Spain

Taiwan

Kaohsiung, Taiwan

Taichung City, Taiwan

Taichung, Taiwan

Taoyuan, Taiwan

Sponsors and Collaborators

Janssen Research & Development, LLC

Investigators

• Study Director: Janssen Research & Development, LLC Clinical Trial; Janssen Research & Development, LLC

  Study Documents (Full-Text)

Documents provided by Janssen Research & Development, LLC:

Study Protocol  [PDF] January 18, 2017

Statistical Analysis Plan  [PDF] March 22, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

van Vollenhoven RF, Hahn BH, Tsokos GC, Lipsky P, Gordon RM, Fei K, Lo KH, Chevrier M, Rose S, Berry P, Yao Z, Karyekar CS, Zuraw Q. Efficacy and Safety of Ustekinumab in Patients With Active Systemic Lupus Erythematosus: Results of a Phase II Open-label Extension Study. J Rheumatol. 2022 Apr;49(4):380-387. doi: 10.3899/jrheum.210805. Epub 2021 Dec 1.

Hannon CW, McCourt C, Lima HC, Chen S, Bennett C. Interventions for cutaneous disease in systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Mar 9;3:CD007478. doi: 10.1002/14651858.CD007478.pub2.

Cesaroni M, Seridi L, Loza MJ, Schreiter J, Sweet K, Franks C, Ma K, Orillion A, Campbell K, M Gordon R, Branigan P, Lipsky P, van Vollenhoven R, Hahn BH, Tsokos GC, Chevrier M, Rose S, Baribaud F, Jordan J. Suppression of Serum Interferon-γ Levels as a Potential Measure of Response to Ustekinumab Treatment in Patients With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2021 Mar;73(3):472-477. doi: 10.1002/art.41547. Epub 2021 Feb 1.

van Vollenhoven RF, Hahn BH, Tsokos GC, Lipsky P, Fei K, Gordon RM, Gregan I, Lo KH, Chevrier M, Rose S. Maintenance of Efficacy and Safety of Ustekinumab Through One Year in a Phase II Multicenter, Prospective, Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Patients With Active Systemic Lupus Erythematosus. Arthritis Rheumatol. 2020 May;72(5):761-768. doi: 10.1002/art.41179. Epub 2020 Apr 1.

van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, Werth VP, Gordon RM, Zhou B, Hsu B, Chevrier M, Triebel M, Jordan JL, Rose S. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet. 2018 Oct 13;392(10155):1330-1339. doi: 10.1016/S0140-6736(18)32167-6. Epub 2018 Sep 21.

• Responsible Party: Janssen Research & Development, LLC
• ClinicalTrials.gov Identifier: NCT02349061
• Other Study ID Numbers: CR106661; CNTO1275SLE2001 ( Other Identifier: Janssen Research & Development, LLC ); 2014-005000-19 ( EudraCT Number )
• First Posted: January 28, 2015
• Results First Posted: June 12, 2018
• Last Update Posted: March 24, 2020
• Last Verified: March 2020

• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Research & Development, LLC:

Systemic Lupus Erythematosus; Ustekinumab

Additional relevant MeSH terms:

Lupus Erythematosus, Systemic; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Ustekinumab; Dermatologic Agents