Psoriatic Arthritis
Conditions
Keywords
Psoriatic arthritis, CNTO 1275, Ustekinumab, Interleukin-23, IL-12, IL-23, Monoclonal antibodies
Brief summary
The purpose of this study is to evaluate the effectiveness and safety of CNTO 1275 (ustekinumab) in patients with psoriatic arthritis.
Detailed description
This study is a randomized (the study drug is assigned by chance), double-blind (neither physician nor the patient knows the treatment that the patient receives), parallel-group (each group of patients will be treated at the same time), multicenter study to evaluate the effectiveness and safety of CNTO 1275 compared to placebo in the treatment of patients with active psoriatic arthritis. Patients will be randomized in 1:1 ratio to 1 of 2 treatment groups (CNTO 1275 63 mg and placebo). Patients will be randomly assigned to receive study medication up to Week 12 and will be followed through Week 36 to monitor safety and efficacy. Patients randomly assigned to placebo will crossover to receive CNTO 1275 63 mg at Weeks 12 and 16. Patients randomly assigned to CNTO 1275 will receive placebo at Weeks 12 and 16 to maintain the blind. The duration of participation for an individual patient in the study will be up to 36 weeks.
Interventions
DRUGCNTO 1275 63 mg
The patients will receive 90 mg (or 63 mg after filtration) subcutaneous injection on Weeks 0, 1, 2, and 3; Placebo subcutaneous injection on Weeks 12 and 16.
DRUGPlacebo
The patients will receive placebo subcutaneous injection on Weeks 0, 1, 2, and 3; At weeks 12 and 16 the patients will receive CNTo1275 90 mg (or 63 mg after filtration) subcutaneous injection
Sponsors
Centocor, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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 active psoriatic arthritis for at least 6 months prior to administration of first study injection * Have an active plaque psoriasis (defined as a lesion of at least 2 cm in diameter), but not in armpits, on chest between breasts or groin * Women of childbearing potential and all men must be using an effective method of birth control measures (eg, abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, or surgical sterilization) and must agree to continue to use such measures until 12 months after receiving the last injection of study agent * Have an active arthritis despite disease-modifying anti-rheumatic drugs (DMARD) such as leflunomide, gold, sulfasalazine, but not including methotrexate) or non-steroidal anti-inflammatory agents (NSAID) such as aspirin, ibuprofen, naproxen) therapy. DMARD therapy is defined as taking a DMARD for at least 3 months, or evidence of not tolerating DMARD. NSAID therapy is defined as taking an NSAID for at least 4 weeks * If the patients are using methotrexate (MTX), they should have started treatment at least 3 months prior to the first administration of study agent and should have no serious toxic side effects attributable to MTX * Have no signs or symptoms suggestive of active tuberculosis upon medical history, physical examination and chest X-ray
Exclusion criteria
* Have received DMARDs, other than methotrexate, within 4 weeks prior to the randomization visit * Have used any biologic within the previous 3 months or 5 times the half-life of the biologic, whichever is longer * Have received any oral, intravenous or intramuscular medications/treatments that could affect psoriasis (including, but not limited to, oral or injectable corticosteroids, retinoids, 1,25 dihydroxy vitamin D3 and analogues, psoralens, sulfasalazine, hydroxyurea, fumaric acid derivatives, or phototherapy) within 4 weeks of the randomization visit and/or have used topical medications/treatments that could affect psoriasis (eg, corticosteroids, anthralin, calcipotriene, topical vitamin D derivatives, retinoids, tazarotene, methoxsalen, trimethylpsoralens) within 2 weeks of the randomization visit * Have a history of chronic or recurrent infectious disease, including but not limited to chronic renal infection, chronic chest infection (eg, bronchiectasis), recurrent urinary tract infection (recurrent pyelonephritis or chronic nonremitting cystitis), or open, draining, or infected skin wounds or ulcers * Have a history of latent or active granulomatous infection, including tuberculosis (TB), histoplasmosis, or coccidioidomycosis, prior to screening * Have current signs or symptoms of severe, progressive, or uncontrolled kidney, liver, blood, intestinal, hormonal, lung, heart, nervous, brain, or psychiatric disease * Have any known cancer or have a history of cancer within the previous 5 years (with the following exception: have had basal cell carcinoma or squamous cell carcinoma in situ of the skin that has been treated, with no evidence of recurrence)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an American College of Rheumatology (ACR) 20 Response at Week 12 | Week 0 to Week 12 | ACR 20 response is an improvement of greater than or equal to 20 percentage in both tender and swollen joint count and in 3 to 5 assessments (patient's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an American College of Rheumatology (ACR) 50 Response at Week 12 | Week 12 | ACR 50 response is an improvement of greater than or equal to 50 percentage in both tender and swollen joint count and in 3 to 5 assessments (patient's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]). |
| Number of Participants With an American College of Rheumatology (ACR) 70 Response at Week 12 | Week 12 | ACR 70 response is an improvement of greater than or equal to 70 percentage in both tender and swollen joint count and in 3 to 5 assessments (patient's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]). |
| Change in Health Assessment Questionnaire (HAQ) at Week 12 | Week 0 to Week 12 | The HAQ is a 20-question instrument 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, indicating no difficulty, to 3, indicating inability to perform a task in that area based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores. |
| Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent at Week 12 | Week 12 | Number of participants achieving greater than or equal to 75 perccentage mprovement PASI at Week 12. PASI is widely used tool for the measurement of severity of psoriasis. This is a test of how bad person's psoriasis is. The combine redness, scaling, and thickness, as well as overall body involvement determine the PASI score. The scale ranges from 0 (best) to 72 (worst). |
| Change in Dermatology Life Quality Index (DLQI) at Week 12 | Week 0 to Week 12 | Change in Dermatology Life Quality Index (DLQI) from baseline at Week 12. The DLQI is a 10 item questionnaire, is designed to assess the impact of the disease on a participant's quality of life, can be used to assess 6 different aspects that may affect quality of life: symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment. The score ranges from 0 (better quality of life) to 30 (worse quality of life). |
Countries
Canada, Denmark, Finland, Switzerland, United States
Participant flow
Recruitment details
146 participants were randomly assigned to receive either placebo or ustekinumab (CNTO 1275) at 24 sites in North America and Europe.
Participants by arm
| Arm | Count |
|---|---|
| Group I: Placebo Participants received subcutaneous (SC) placebo injection at Weeks 0, 1,2, and 3. At Week (Wk) 12 and Wk 16, placebo participants crossed over to receive ustekinumab (CNTO 1275) SC. | 70 |
| Group II: Ustekinumab x 4 Participants received SC injection of ustekinumab 90 mg at Wk 0,1,2, and 3. At Wk 12 and Wk 16, participants received placebo SC to maintain the blind. After the first 36 participants were randomized, Centocor became aware that some vials of other study agents not used in this study contained black particulate matter and the filtration procedure was implemented. The resulting dose of ustekinumab after filtration was approximately 0.70 mL, equivalent to 63 mg. | 76 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| After Controlled Period | Adverse Event | 0 | 0 | 2 | 1 |
| After Controlled Period | Lack of Efficacy | 0 | 0 | 1 | 1 |
| After Controlled Period | Lost to Follow-up | 0 | 0 | 1 | 0 |
| After Controlled Period | Withdrew consent | 0 | 0 | 1 | 0 |
| Controlled Period | Adverse Event | 4 | 1 | 0 | 0 |
| Controlled Period | Lack of Efficacy | 4 | 2 | 0 | 0 |
| Controlled Period | Lost to Follow-up | 2 | 0 | 0 | 0 |
| Controlled Period | Withdrew consent | 3 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Group I: Placebo | Group II: Ustekinumab x 4 | Total |
|---|---|---|---|
| Age Continuous | 47.1 years STANDARD_DEVIATION 10.52 | 50.2 years STANDARD_DEVIATION 11.23 | 48.7 years STANDARD_DEVIATION 10.97 |
| Sex: Female, Male Female | 33 Participants | 31 Participants | 64 Participants |
| Sex: Female, Male Male | 37 Participants | 45 Participants | 82 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 19 / 70 | 29 / 76 | 19 / 57 | 24 / 74 |
| serious Total, serious adverse events | 3 / 70 | 0 / 76 | 4 / 57 | 2 / 74 |
Outcome results
Primary
Number of Participants With an American College of Rheumatology (ACR) 20 Response at Week 12
ACR 20 response is an improvement of greater than or equal to 20 percentage in both tender and swollen joint count and in 3 to 5 assessments (patient's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]).
Time frame: Week 0 to Week 12
Population: Intent to treat. All participants randomized were included in the analysis according to the assigned treatment groups. Participant is considered a non- responder if the participant has used any pre-specified prohibited medications or discontinued due to lack of efficacy or participant who have no data for all ACR components at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Number of Participants With an American College of Rheumatology (ACR) 20 Response at Week 12 | 10 Participants |
| Group II: Ustekinumab x 4 | Number of Participants With an American College of Rheumatology (ACR) 20 Response at Week 12 | 32 Participants |
Comparison: Hypothesis: No difference between ustekinumab x 4 and placebo at a significant level of 0.05. Sample Size and power: With 70 partcipants in each treatment group, 5000 repetitions. Assuming a 20% ACR20 response in placebo participants regardless of prior anti-TNF exposure and a 35% ACR 20 and 45% ACR20 response in ustekinumab group for participants who had prior anti-TNF exposure, and who had no prior anti-TNF exposures, the power to detect the treatment difference is 0.85.p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi-square
Secondary
Change in Dermatology Life Quality Index (DLQI) at Week 12
Change in Dermatology Life Quality Index (DLQI) from baseline at Week 12. The DLQI is a 10 item questionnaire, is designed to assess the impact of the disease on a participant's quality of life, can be used to assess 6 different aspects that may affect quality of life: symptoms and feelings, daily activities, leisure, work or school performance, personal relationships, and treatment. The score ranges from 0 (better quality of life) to 30 (worse quality of life).
Time frame: Week 0 to Week 12
Population: All participants randomized with baseline ≥ 3% body surface area psoriatic involvement were included in the analysis according to the assigned treatment groups. Zero change is imputed if the participant has used any pre-specified prohibited medications or discontinued due to lack of efficacy. Other missing data were not imputed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Change in Dermatology Life Quality Index (DLQI) at Week 12 | 0.00 Scores on scale |
| Group II: Ustekinumab x 4 | Change in Dermatology Life Quality Index (DLQI) at Week 12 | -6.0 Scores on scale |
Comparison: Hypothesis: No difference between ustekinumab x 4 and placebo at asignificant level of 0.05.p-value: <0.001ANOVA on van der Waerden normal scores
Secondary
Change in Health Assessment Questionnaire (HAQ) at Week 12
The HAQ is a 20-question instrument 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, indicating no difficulty, to 3, indicating inability to perform a task in that area based on the worst score from the questions that pertain to that task. The HAQ score is determined by the average of the 8 scores.
Time frame: Week 0 to Week 12
Population: Participants were included in the analysis according to the assigned treatment groups. Zero change is imputed if the participant has used any pre-specified prohibited medications or discontinued due to lack of efficacy. Other missing data were not imputed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Change in Health Assessment Questionnaire (HAQ) at Week 12 | 0.00 Scores on scale |
| Group II: Ustekinumab x 4 | Change in Health Assessment Questionnaire (HAQ) at Week 12 | -0.25 Scores on scale |
Comparison: Hypothesis: No difference between ustekinumab x 4 and placebo at a significant level of 0.05.p-value: <0.001ANOVA on van der Waerden normal scores
Secondary
Number of Participants With an American College of Rheumatology (ACR) 50 Response at Week 12
ACR 50 response is an improvement of greater than or equal to 50 percentage in both tender and swollen joint count and in 3 to 5 assessments (patient's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]).
Time frame: Week 12
Population: Intent to treat. All participants randomized were included in the analysis according to the assigned treatment groups. Participant is considered a non- responder if the participant has used any pre-specified prohibited medications or discontinued due to lack of efficacy or participant who have no data for all ACR components at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Number of Participants With an American College of Rheumatology (ACR) 50 Response at Week 12 | 5 Participants |
| Group II: Ustekinumab x 4 | Number of Participants With an American College of Rheumatology (ACR) 50 Response at Week 12 | 19 Participants |
Comparison: Hypothesis: No difference between Group II and Group I at a significant level of 0.05.p-value: 0.004Cochran-Mantel-Haenszel (CMH) chi-square
Secondary
Number of Participants With an American College of Rheumatology (ACR) 70 Response at Week 12
ACR 70 response is an improvement of greater than or equal to 70 percentage in both tender and swollen joint count and in 3 to 5 assessments (patient's assessment of pain visual analog scale \[VAS\] with 0, no pain to 10, worst pain; patient's and physician's global assessment of disease activity VAS scales: overall disease activity \[0, very well to 10, very poor and 0, no arthritis activity to 10, extremely active, respectively\]; Health Assessment Questionnaire \[HAQ\]: 20-questions on life activities \[0, no difficulty to 3, inability to perform a task\]; C-reactive protein\[CRP\]).
Time frame: Week 12
Population: Intent to treat. All participant randomized were included in the analysis according to the assigned treatment groups. Participant is considered a non- responder if the participant has used any pre-specified prohibited medications or discontinued due to lack of efficacy or participant who have no data for all ACR components at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Number of Participants With an American College of Rheumatology (ACR) 70 Response at Week 12 | 0 Participants |
| Group II: Ustekinumab x 4 | Number of Participants With an American College of Rheumatology (ACR) 70 Response at Week 12 | 8 Participants |
Comparison: Hypothesis: No difference between ustekinumab x 4 and placebo at a significant level of 0.05.p-value: 0.005Cochran-Mantel-Haenszel (CMH) chi-square
Secondary
Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent at Week 12
Number of participants achieving greater than or equal to 75 perccentage mprovement PASI at Week 12. PASI is widely used tool for the measurement of severity of psoriasis. This is a test of how bad person's psoriasis is. The combine redness, scaling, and thickness, as well as overall body involvement determine the PASI score. The scale ranges from 0 (best) to 72 (worst).
Time frame: Week 12
Population: All participants randomized with baseline ≥ 3% body surface area (BSA) psoriatic involvement and with evaluable measurement are included in the analysis according to the assigned treatment groups. Participant is considered a non- responder if the participant has used any pre-specified prohibited medications or discontinued due to lack of efficacy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent at Week 12 | 3 Participants |
| Group II: Ustekinumab x 4 | Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent at Week 12 | 33 Participants |
Comparison: Hypothesis: No difference between ustekinumab x 4 and placebo at a significant level of 0.05.p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi-square