Arthritis, Psoriatic
Conditions
Keywords
Ustekinumab, CNTO 1275, Stelara, Psoriatic Arthritis, Psoriasis, TNF alpha
Brief summary
The purpose of this study is to evaluate the efficacy (improvement of signs and symptoms) and safety of ustekinumab in patients with psoriatic arthritis.
Detailed description
This study is a randomized (patients are assigned different treatments based on chance), double-blind (neither the patient nor the physician knows whether drug or placebo is being taken, or at what dosage), parallel-group, multicenter study to evaluate the effectiveness and safety of ustekinumab compared to placebo in the treatment of patients with active psoriatic arthritis who have or are currently receiving treatment with a disease-modifying antirheumatic drug (DMARD) and/or a nonsteroidal anti-inflammatory drug (NSAID), including those who have previously received anti-tumor necrosis factor (anti-TNF) agents \[(examples are infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira)\]. The primary effectiveness endpoint will be measured by the reduction in signs and symptoms of arthritis, as defined by 20% improvement from baseline in American College of Rheumatology (ACR) measurements of arthritis at Week 24. The study will additionally look at higher levels of joint improvement (ie, 50% or 70% improvement from baseline) and improvement in activity and quality of life, as well as the impact of ustekinumab on psoriatic skin lesions. Safety assessments will be performed throughout the study and include obtaining and evaluating laboratory tests, vital signs (eg, blood pressure) and the occurrence and severity of adverse events (side effects). Patients will be assigned to one of three treatment groups. Patients will receive either 45 mg ustekinumab, 90 mg ustekinumab, or placebo at Weeks 0, 4 and every 12 weeks until Week 40. Patients who do not have \>=5% improvement in their disease (tender and swollen joints) at Week 16 may be eligible to receive an increase or change to their ustekinumab dosage. Ustekinumab 45 mg, 90 mg, or placebo subcutaneous injections at Weeks 0 and 4 followed by every-12-week dosing with the last dose at Week 40. Early escape possibility at Week 16. Patients randomized to placebo will crossover to receive ustekinumab at Weeks 24 and 28 followed by every-12-week dosing with the last dose at Week 40. Expected duration of exposure to study agent including follow up for safety is 60 weeks.
Interventions
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have had a documented diagnosis of psoriatic arthritis (PsA) at least 6 months * Have a diagnosis of active PsA at the time of entry into the study with at least 5 tender and 5 swollen joints at baseline * May have previously received at least 8 weeks of etanercept, adalimumab, golimumab or certolizumab pegol or at least 14 weeks of infliximab or proven inability to tolerate anti-TNF therapy for 8-14 weeks * If the patient is using methotrexate, they should have started treatment at a dose not to exceed 25 mg/week at least 3 months prior to the beginning of the study and should have no serious toxic side effects attributable to methotrexate
Exclusion criteria
* Have other inflammatory diseases, including but not limited to rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease * Have used any therapeutic agent targeted at reducing IL-12 or IL-23, including but not limited to ustekinumab and ABT-874 * Have used infliximab, golimumab or certolizumab pegol within 12 weeks of first study drug injection, or etanercept or adalimumab within 8 weeks of first study drug injection * Have a medical history of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to screening * Have any known malignancy or have a history of malignancy (with the exception of basal cell carcinoma, squamous cell carcinoma in situ of the skin, or cervical carcinoma in situ that has been treated with no evidence of recurrence, or squamous cell carcinoma of the skin that has been treated with no evidence of recurrence within 5 years of the beginning of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24. | Week 24 | An ACR 20 response is defined as a greater than or equal to 20 percent improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and greater than or equal to 20 percent improvement in 3 of the following 5 assessments: 1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm), 2) Participant's global assessment of disease activity by VAS (0-10 cm), 3) Physician's global assessment of disease activity by VAS (0-10 cm) 4) Participant's assessment of physical function as measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) (score of 0-3 in 8 functional areas) and 5) C reactive protein. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 24 in the Disability Index Score as Measured With the Disability Index of the Health Assessment Questionnaire (HAQ-DI) | Day 1 (Baseline) and Week 24 | HAQ-DI is 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0 (no difficulty), to 3 (inability to perform a task in that area). The average score across the functional areas yields an overall HAQ-DI score which ranges from 0 (no disability) to 3 (completely disabled). In psoriatic arthritis, a decrease in score of 0.30 indicates clinically meaningful improvement. |
| Percentage of Participants (With >= 3% Baseline Body Surface Area (BSA) Psoriatic Involvement) Who Achieved a Psoriasis Area and Severity Index 75 (PASI 75) Response at Week 24 | Week 24 | The PASI is a physician-administered assessment tool used for assessing and grading the severity of psoriatic lesions and their response to therapy. The PASI produces a numeric score that can range from 0 (no disease) to 72 (maximal disease). A PASI 75 response is defined as greater than or equal to 75 percent improvement in PASI score from baseline. |
| Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24 | Week 24 | An ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and greater than or equal to 50 percent improvement in 3 of the following 5 assessments: 1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm), 2) Participant's global assessment of disease activity by VAS (0-10 cm), 3) Physician's global assessment of disease activity by VAS (0-10 cm) 4) Participant's assessment of physical function as measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) (score of 0-3 in 8 functional areas) and 5) C reactive protein. |
| Change From Baseline to Week 24 in Total Modified Van Der Heijde-Sharp (vdH-S) Score for the Combined Radiographic Data From Studies CNTO1275PSA3001 and CNTO1275PSA3002 | Day 1 (Baseline) and Week 24 | The modified vdH-S score is a radiographic evaluation of hand and feet erosions and joint space narrowing (JSN) for 20 joints per hand and 6 joints per foot with a total score ranging from 0 (best) to 528 (worst = worst possible erosion score of 320 + worst possible JSN score of 208). Higher scores and positive score changes indicate more radiographic damage and radiographic progression, respectively. As per protocol, the analysis for this outcome measure used pooled data from 2 studies (CNTO1275PSA3001 and PSA3002) because initial power assumptions showed that 900 participants would be required to evaluate the impact of ustekinumab on structural damage (SD) progression. The 2 studies, (which had similar study designs and dosing regimens and differed only with regards to prior exposure to anti-TNFα therapies), were intended to independently measure efficacy in terms of signs, symptoms and physical function, while effects on SD progression would be provided from an integrated analysis. |
| Percentage of Participants With American College of Rheumatology (ACR) 70 Response at Week 24 | Week 24 | An ACR 70 response is defined as a greater than or equal to 70 percent improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and greater than or equal to 70 percent improvement in 3 of the following 5 assessments: 1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm), 2) Participant's global assessment of disease activity by VAS (0-10 cm), 3) Physician's global assessment of disease activity by VAS (0-10 cm) 4) Participant's assessment of physical function as measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) (score of 0-3 in 8 functional areas) and 5) C reactive protein. |
Countries
Austria, Canada, France, Germany, Hungary, Poland, Russia, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received subcutaneous (SC) injections of placebo at Weeks 0, 4, 16, and 20. At Week 24 participants crossed over to receive SC injections of ustekinumab 45 mg at Weeks 24 and 28 and every 12 weeks thereafter with the last dose at Week 40. If early escape, SC injections of 45 mg ustekinumab were given at Weeks 16, 20, and 28 and every 12 weeks thereafter with the last dose at Week 40. For participants entering early escape, a SC placebo injection was given at Week 24 to maintain the blind. | 104 |
| Ustekinumab 45 mg Participants received SC injections of ustekinumab 45 mg at Weeks 0 and 4 and every 12 weeks thereafter with the last dose at Week 40. If early escape, SC injections of 90 mg ustekinumab were given at Week 16 and every 12 weeks thereafter with the last dose at Week 40. Participants received SC injections of placebo at Weeks 20 and 24 to maintain the blind. | 103 |
| Ustekinumab 90 mg Participants received SC injections of ustekinumab 90 mg at Weeks 0 and 4 and every 12 weeks thereafter with the last dose at Week 40. If early escape, the same dosage schedule continued. Participants received SC injections of placebo at Weeks 20 and 24 to maintain the blind. | 105 |
| Total | 312 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 7 | 4 |
| Overall Study | Lack of Efficacy | 13 | 8 | 10 |
| Overall Study | Lost to Follow-up | 1 | 0 | 3 |
| Overall Study | Other | 0 | 1 | 2 |
| Overall Study | Withdrawal by Subject | 5 | 3 | 5 |
Baseline characteristics
| Characteristic | Placebo | Ustekinumab 45 mg | Ustekinumab 90 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 47.6 years STANDARD_DEVIATION 11.19 | 48 years STANDARD_DEVIATION 11.21 | 48.2 years STANDARD_DEVIATION 12.36 | 47.9 years STANDARD_DEVIATION 11.57 |
| Sex: Female, Male Female | 53 Participants | 55 Participants | 56 Participants | 164 Participants |
| Sex: Female, Male Male | 51 Participants | 48 Participants | 49 Participants | 148 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 | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 104 | 16 / 103 | 19 / 104 | 5 / 60 | 10 / 80 | 16 / 100 | 24 / 99 |
| serious Total, serious adverse events | 5 / 104 | 0 / 103 | 1 / 104 | 0 / 60 | 2 / 80 | 6 / 100 | 6 / 99 |
Outcome results
Primary
Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24.
An ACR 20 response is defined as a greater than or equal to 20 percent improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and greater than or equal to 20 percent improvement in 3 of the following 5 assessments: 1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm), 2) Participant's global assessment of disease activity by VAS (0-10 cm), 3) Physician's global assessment of disease activity by VAS (0-10 cm) 4) Participant's assessment of physical function as measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) (score of 0-3 in 8 functional areas) and 5) C reactive protein.
Time frame: Week 24
Population: All participants randomly assigned to a treatment group were included in the efficacy analysis regardless of whether they received the assigned treatment. For early escape, data at or prior to Week 16 were carried forward through Week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24. | 20.2 Percentage of participants |
| Ustekinumab 45 mg | Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24. | 43.7 Percentage of participants |
| Ustekinumab 90 mg | Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24. | 43.8 Percentage of participants |
| All Ustekinumab Combined | Percentage of Participants With American College of Rheumatology (ACR) 20 Response at Week 24. | 43.8 Percentage of participants |
p-value: <0.001re-randomization test
p-value: <0.001re-randomization test
p-value: <0.001re-randomization test
Secondary
Change From Baseline to Week 24 in the Disability Index Score as Measured With the Disability Index of the Health Assessment Questionnaire (HAQ-DI)
HAQ-DI is 20-question instrument that assesses the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area are scored from 0 (no difficulty), to 3 (inability to perform a task in that area). The average score across the functional areas yields an overall HAQ-DI score which ranges from 0 (no disability) to 3 (completely disabled). In psoriatic arthritis, a decrease in score of 0.30 indicates clinically meaningful improvement.
Time frame: Day 1 (Baseline) and Week 24
Population: All participants randomly assigned to a treatment group were included in the efficacy analysis regardless of whether they received the assigned treatment. For early escape, data at or prior to Week 16 were carried forward through Week 24.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 24 in the Disability Index Score as Measured With the Disability Index of the Health Assessment Questionnaire (HAQ-DI) | -0.03 Score on a scale | Standard Deviation 0.38 |
| Ustekinumab 45 mg | Change From Baseline to Week 24 in the Disability Index Score as Measured With the Disability Index of the Health Assessment Questionnaire (HAQ-DI) | -0.21 Score on a scale | Standard Deviation 0.461 |
| Ustekinumab 90 mg | Change From Baseline to Week 24 in the Disability Index Score as Measured With the Disability Index of the Health Assessment Questionnaire (HAQ-DI) | -0.22 Score on a scale | Standard Deviation 0.436 |
| All Ustekinumab Combined | Change From Baseline to Week 24 in the Disability Index Score as Measured With the Disability Index of the Health Assessment Questionnaire (HAQ-DI) | -0.21 Score on a scale | Standard Deviation 0.447 |
p-value: 0.002re-randomization test
p-value: <0.001re-randomization test
p-value: <0.001re-randomization test
Secondary
Change From Baseline to Week 24 in Total Modified Van Der Heijde-Sharp (vdH-S) Score for the Combined Radiographic Data From Studies CNTO1275PSA3001 and CNTO1275PSA3002
The modified vdH-S score is a radiographic evaluation of hand and feet erosions and joint space narrowing (JSN) for 20 joints per hand and 6 joints per foot with a total score ranging from 0 (best) to 528 (worst = worst possible erosion score of 320 + worst possible JSN score of 208). Higher scores and positive score changes indicate more radiographic damage and radiographic progression, respectively. As per protocol, the analysis for this outcome measure used pooled data from 2 studies (CNTO1275PSA3001 and PSA3002) because initial power assumptions showed that 900 participants would be required to evaluate the impact of ustekinumab on structural damage (SD) progression. The 2 studies, (which had similar study designs and dosing regimens and differed only with regards to prior exposure to anti-TNFα therapies), were intended to independently measure efficacy in terms of signs, symptoms and physical function, while effects on SD progression would be provided from an integrated analysis.
Time frame: Day 1 (Baseline) and Week 24
Population: Analysis included: (1) combined data from studies CNTO1275PSA3001 (NCT01009086) and CNTO1275PSA3002 (NCT01077362) and (2) all participants randomly assigned to a treatment group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline to Week 24 in Total Modified Van Der Heijde-Sharp (vdH-S) Score for the Combined Radiographic Data From Studies CNTO1275PSA3001 and CNTO1275PSA3002 | 0.97 Score on a scale | Standard Deviation 3.852 |
| Ustekinumab 45 mg | Change From Baseline to Week 24 in Total Modified Van Der Heijde-Sharp (vdH-S) Score for the Combined Radiographic Data From Studies CNTO1275PSA3001 and CNTO1275PSA3002 | 0.40 Score on a scale | Standard Deviation 2.11 |
| Ustekinumab 90 mg | Change From Baseline to Week 24 in Total Modified Van Der Heijde-Sharp (vdH-S) Score for the Combined Radiographic Data From Studies CNTO1275PSA3001 and CNTO1275PSA3002 | 0.39 Score on a scale | Standard Deviation 2.403 |
| All Ustekinumab Combined | Change From Baseline to Week 24 in Total Modified Van Der Heijde-Sharp (vdH-S) Score for the Combined Radiographic Data From Studies CNTO1275PSA3001 and CNTO1275PSA3002 | 0.40 Score on a scale | Standard Deviation 2.26 |
p-value: 0.017re-randomization test
p-value: <0.001re-randomization test
p-value: <0.001re-randomization test
Secondary
Percentage of Participants (With >= 3% Baseline Body Surface Area (BSA) Psoriatic Involvement) Who Achieved a Psoriasis Area and Severity Index 75 (PASI 75) Response at Week 24
The PASI is a physician-administered assessment tool used for assessing and grading the severity of psoriatic lesions and their response to therapy. The PASI produces a numeric score that can range from 0 (no disease) to 72 (maximal disease). A PASI 75 response is defined as greater than or equal to 75 percent improvement in PASI score from baseline.
Time frame: Week 24
Population: All participants randomly assigned to a treatment group were included in the efficacy analysis regardless of whether they received the assigned treatment. For early escape, data at or prior to Week 16 were carried forward through Week 24. Only participants with \>=3% baseline BSA psoriatic involvement were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants (With >= 3% Baseline Body Surface Area (BSA) Psoriatic Involvement) Who Achieved a Psoriasis Area and Severity Index 75 (PASI 75) Response at Week 24 | 5.0 Percentage of participants |
| Ustekinumab 45 mg | Percentage of Participants (With >= 3% Baseline Body Surface Area (BSA) Psoriatic Involvement) Who Achieved a Psoriasis Area and Severity Index 75 (PASI 75) Response at Week 24 | 51.3 Percentage of participants |
| Ustekinumab 90 mg | Percentage of Participants (With >= 3% Baseline Body Surface Area (BSA) Psoriatic Involvement) Who Achieved a Psoriasis Area and Severity Index 75 (PASI 75) Response at Week 24 | 55.6 Percentage of participants |
| All Ustekinumab Combined | Percentage of Participants (With >= 3% Baseline Body Surface Area (BSA) Psoriatic Involvement) Who Achieved a Psoriasis Area and Severity Index 75 (PASI 75) Response at Week 24 | 53.4 Percentage of participants |
p-value: <0.001re-randomization test
p-value: <0.001re-randomization test
p-value: <0.001re-randomization test
Secondary
Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24
An ACR 50 response is defined as a greater than or equal to 50 percent improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and greater than or equal to 50 percent improvement in 3 of the following 5 assessments: 1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm), 2) Participant's global assessment of disease activity by VAS (0-10 cm), 3) Physician's global assessment of disease activity by VAS (0-10 cm) 4) Participant's assessment of physical function as measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) (score of 0-3 in 8 functional areas) and 5) C reactive protein.
Time frame: Week 24
Population: All participants randomly assigned to a treatment group were included in the efficacy analysis regardless of whether they received the assigned treatment. For early escape, data at or prior to Week 16 were carried forward through Week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24 | 6.7 Percentage of participants |
| Ustekinumab 45 mg | Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24 | 17.5 Percentage of participants |
| Ustekinumab 90 mg | Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24 | 22.9 Percentage of participants |
| All Ustekinumab Combined | Percentage of Participants With American College of Rheumatology (ACR) 50 Response at Week 24 | 20.2 Percentage of participants |
p-value: 0.018re-randomization test
p-value: <0.001re-randomization test
p-value: 0.002re-randomization test
Secondary
Percentage of Participants With American College of Rheumatology (ACR) 70 Response at Week 24
An ACR 70 response is defined as a greater than or equal to 70 percent improvement from baseline in swollen (66 joints) and tender (68 joints) joint counts and greater than or equal to 70 percent improvement in 3 of the following 5 assessments: 1) Participant's assessment of pain by Visual Analog Scale (VAS) (0-10 cm), 2) Participant's global assessment of disease activity by VAS (0-10 cm), 3) Physician's global assessment of disease activity by VAS (0-10 cm) 4) Participant's assessment of physical function as measured by the Disability Index of the Health Assessment Questionnaire (HAQ-DI) (score of 0-3 in 8 functional areas) and 5) C reactive protein.
Time frame: Week 24
Population: All participants randomly assigned to a treatment group were included in the efficacy analysis regardless of whether they received the assigned treatment. For early escaped, data at or prior to Week 16 were carried forward through Week 24.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With American College of Rheumatology (ACR) 70 Response at Week 24 | 2.9 Percentage of participants |
| Ustekinumab 45 mg | Percentage of Participants With American College of Rheumatology (ACR) 70 Response at Week 24 | 6.8 Percentage of participants |
| Ustekinumab 90 mg | Percentage of Participants With American College of Rheumatology (ACR) 70 Response at Week 24 | 8.6 Percentage of participants |
| All Ustekinumab Combined | Percentage of Participants With American College of Rheumatology (ACR) 70 Response at Week 24 | 7.7 Percentage of participants |
p-value: 0.171re-randomization
p-value: 0.06re-randomization test
p-value: 0.094re-randomization