Lupus Erythematosus, Systemic
Conditions
Keywords
Systemic Lupus Erythematosus, Ustekinumab
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).
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.
Interventions
DRUGUstekinumab IV
Weight-range based dosing of approximately 6 mg/kg of ustekinumab intravenously at Week 0.
DRUGPlacebo Infusion
Placebo intravenously at Week 0.
DRUGPlacebo SC
Placebo subcutaneously at Weeks 8 and 16.
DRUGUstekinumab SC
Ustekinumab 90 mg subcutaneously every 8 weeks up to Week 40 and up to Week 104 in study extension (for eligible participants)
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.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Systemic Lupus Erythematosus Responder Index (SRI-4) Composite Response (CR) at Week 24 | 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
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) Score at Week 24 | 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. |
| Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24 | 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). |
| Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24 | 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'). |
| Change From Baseline in Number of Joints With Pain and Signs of Inflammation at Week 24 | 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). |
Countries
Argentina, Australia, Germany, Hungary, Mexico, Poland, Spain, Taiwan, United States
Participant flow
Pre-assignment details
166 participants were screened during the study, 102 were enrolled/randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| Placebo - Ustekinumab Participants received placebo matched to ustekinumab intravenously (IV) at Week 0 then followed by placebo subcutaneously (SC) at Week 8 and 16. At Week 24, participants who completed were crossed-over to receive ustekinumab 90 milligram (mg) SC at Weeks 24, 32, and 40 followed by safety follow-up through Week 56 in a blinded fashion for 16 weeks after last study agent SC administration. | 42 |
| Ustekinumab Participants received an initial body weight range based IV dose approximating 6 milligram per kilogram (mg/kg) of ustekinumab at Week 0 followed by 90 mg SC administered every 8 weeks (q8w) at Weeks 8 and 16. Participants who completed placebo controlled period (PCP) continued to receive ustekinumab 90 mg at Weeks 24, 32, and 40 followed by safety follow-up for 16 weeks after last study agent SC administration. Per the amended study design, open-label ustekinumab 90 mg q8w SC administration will continue to be provided through Week 104 (study extension) to eligible participants followed by safety follow-up through Week 120. | 60 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Main Study: PCP (Up to Week 24) | Adverse Event | 4 | 3 | 0 |
| Main Study: PCP (Up to Week 24) | Lack of Efficacy | 1 | 0 | 0 |
| Main Study: PCP (Up to Week 24) | Other | 1 | 1 | 0 |
| Main Study: PCP (Up to Week 24) | Physician Decision | 1 | 0 | 0 |
| Main Study: PCP (Up to Week 24) | Withdrawal by Subject | 2 | 0 | 0 |
| Main Study: Week 24 to 56 | Adverse Event | 0 | 2 | 1 |
| Main Study: Week 24 to 56 | Lack of Efficacy | 0 | 1 | 0 |
| Main Study: Week 24 to 56 | Physician Decision | 0 | 0 | 1 |
| Main Study: Week 24 to 56 | Withdrawal by Subject | 0 | 0 | 1 |
| Study Extension (Week 56 to Week 120) | Adverse Event | 0 | 3 | 0 |
| Study Extension (Week 56 to Week 120) | Lack of Efficacy | 0 | 0 | 1 |
| Study Extension (Week 56 to Week 120) | Physician Decision | 0 | 0 | 1 |
| Study Extension (Week 56 to Week 120) | Withdrawal by Subject | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Ustekinumab | Total | Placebo - Ustekinumab |
|---|---|---|---|
| Age, Continuous | 40 years STANDARD_DEVIATION 11.95 | 41.3 years STANDARD_DEVIATION 11.62 | 43.1 years STANDARD_DEVIATION 11.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants | 32 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 70 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 8 Participants | 14 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 Participants | 20 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 11 Participants | 5 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 29 Participants | 50 Participants | 21 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 14 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 70 Participants | 28 Participants |
| Region of Enrollment Argentina | 8 Participants | 12 Participants | 4 Participants |
| Region of Enrollment Australia | 3 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Germany | 3 Participants | 5 Participants | 2 Participants |
| Region of Enrollment Hungary | 4 Participants | 8 Participants | 4 Participants |
| Region of Enrollment Mexico | 5 Participants | 11 Participants | 6 Participants |
| Region of Enrollment Poland | 12 Participants | 19 Participants | 7 Participants |
| Region of Enrollment Spain | 7 Participants | 12 Participants | 5 Participants |
| Region of Enrollment Taiwan, Province Of China | 7 Participants | 13 Participants | 6 Participants |
| Region of Enrollment United States | 11 Participants | 17 Participants | 6 Participants |
| Sex: Female, Male Female | 58 Participants | 93 Participants | 35 Participants |
| Sex: Female, Male Male | 2 Participants | 9 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 42 | 0 / 60 | 0 / 33 | 0 / 56 | 0 / 17 | 0 / 29 |
| other Total, other adverse events | 25 / 42 | 30 / 60 | 21 / 33 | 34 / 56 | 8 / 17 | 22 / 29 |
| serious Total, serious adverse events | 4 / 42 | 5 / 60 | 5 / 33 | 7 / 56 | 1 / 17 | 4 / 29 |
Outcome results
Primary
Percentage of Participants With a Systemic Lupus Erythematosus Responder Index (SRI-4) Composite Response (CR) at 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).
Time frame: Week 24
Population: Full analysis set (FAS) included all the randomized participants who received at least 1 dose (partial or complete, IV or SC) of ustekinumab or placebo.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With a Systemic Lupus Erythematosus Responder Index (SRI-4) Composite Response (CR) at Week 24 | 33.3 Percentage of participants |
| Ustekinumab | Percentage of Participants With a Systemic Lupus Erythematosus Responder Index (SRI-4) Composite Response (CR) at Week 24 | 61.7 Percentage of participants |
p-value: 0.005795% CI: [1.41, 7.63]Regression, Logistic
Secondary
Change From Baseline in Number of Joints With Pain and Signs of Inflammation at 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).
Time frame: Baseline, Week 24
Population: FAS included all the randomized participants who received at least 1 dose (partial or complete, IV or SC) of ustekinumab or placebo. Population included participants with at least 2 affected joints at baseline (2 or more affected joints).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Number of Joints With Pain and Signs of Inflammation at Week 24 | -2.8 Joints | Standard Deviation 7.31 |
| Ustekinumab | Change From Baseline in Number of Joints With Pain and Signs of Inflammation at Week 24 | -4.5 Joints | Standard Deviation 4.42 |
p-value: 0.103295% CI: [-4.78, 0.45]Mixed model repeated measures model
Secondary
Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at 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).
Time frame: Baseline, Week 24
Population: FAS included all the randomized participants who received at least 1 dose (partial or complete, IV or SC) of ustekinumab or placebo. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24 | -1.93 Units on a scale | Standard Deviation 2.168 |
| Ustekinumab | Change From Baseline in Physician's Global Assessment of Disease Activity (PGA) Score at Week 24 | -2.17 Units on a scale | Standard Deviation 1.915 |
p-value: 0.394495% CI: [-1.271, 0.506]Mixed model repeated measures model
Secondary
Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) Score at 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.
Time frame: Baseline, Week 24
Population: FAS included all the randomized participants who received at least 1 dose (partial or complete, IV or SC) of ustekinumab or placebo. Here, 'N' (number of participants analyzed) signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) Score at Week 24 | -3.8 Units on a scale | Standard Deviation 5.39 |
| Ustekinumab | Change From Baseline in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) Score at Week 24 | -4.4 Units on a scale | Standard Deviation 2.91 |
p-value: 0.092995% CI: [-2.94, 0.23]Mixed model repeated measures model
Secondary
Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at 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').
Time frame: Week 24
Population: FAS included all the randomized participants who received at least 1 dose (partial or complete, IV or SC) of ustekinumab or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24 | 14 Participants |
| Ustekinumab | Number of Participants With BILAG-based Combined Lupus Assessment (BICLA) Response at Week 24 | 21 Participants |
p-value: 0.993995% CI: [0.43, 2.34]Regression, Logistic