Psoriasis
Conditions
Keywords
Ustekinumab, CNTO1275, Plaque type Psoriasis, Interleukin-23, IL-23, Psoriasis, Interleukin 12, IL-12
Brief summary
The primary purpose of this study is to evaluate the effectiveness and safety of ustekinumab (CNTO 1275) in the treatment of patients with moderate to severe plaque psoriasis.
Detailed description
This is a randomized (patients are assigned to different treatments based on chance), double blind (neither the patient nor the physician knows whether medication or placebo \[an inactive substance that is compared with a medication to test whether the medication has a real effect in a clinical study\] is being taken, or at what dosage), parallel-group (each group of patients are treated at the same time), multicenter study to determine the effectiveness and safety of two different doses of ustekinumab administered subcutaneously (under the skin) as compared with placebo in patients with moderate to severe plaque-type psoriasis (the most common type of psoriasis). 766 patients will be randomized to Group 1 (ustekinumab 45 mg), Group 2 (ustekinumab 90 mg) and Group 3 (placebo) at Week 0. The study was designed to evaluate the effectiveness and safety of 2 dose regimens of ustekinumab: (1) 45 mg at Weeks 0 and 4 followed by 45 mg every 12 weeks maintenance therapy (treatment designed to help the original primary treatment succeed) and (2) 90 mg at Weeks 0 and 4 followed by 90 mg every 12 weeks maintenance therapy. The study will consist of 4 periods: (1) Placebo-controlled portion of study \[Week 0 to Week 12\] during which the safety and effectiveness of 2 doses (45mg and 90mg) of ustekinumab will be compared to placebo; (2) Placebo crossover and active treatment portion of study \[Week 12 to Week 40\] during which patients randomized to receive placebo at Week 0 will crossover to receive ustekinumab, and all patients will receive active treatment; (3) Randomized withdrawal portion of study \[beginning at Week 40\] during which patients who received ustekinumab \[45mg or 90mg every 12 weeks\] at Week 0 and are responding to it, will be randomized either to placebo or continued maintenance therapy with ustekinumab; and (4) Long-term extension \[from Week 52 to Week 264 (ie, 5 years)\] period during which the safety and effectiveness of ustekinumab long-term use will be evaluated in patients.
Interventions
DRUGustekinumab
Type = exact number, Form = solution for injection, Number = 45 and 90, Unit = mg, Route = subcutaneous (SC) administered at Weeks 0, 4 and 16. Both treatments (45 mg and 90 mg) administered every 12 weeks after Week 16 depending on clinical response.
DRUGplacebo
Form = solution for injection, route = SC administered at Weeks 0 and 4. At Weeks 12 and 16, placebo will be crossed over to receive ustekinumab 45 mg or 90 mg.
Sponsors
Centocor Research & Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with plaque-type psoriasis diagnosed at least 6 months prior and covering at least 10% of total body surface areas * Have psoriasis area-and-severity index score of \>=12 * Patients who are considered by treating dermatologist to be a candidate for phototherapy or systemic treatment of psoriasis * Have no history of latent or active TB
Exclusion criteria
* Currently have nonplaque forms of psoriasis or drug-induced psoriasis * Have any therapeutic agent targeted at reducing IL-12 or IL-23 * Have had a BCG vaccination within the previous 12 months * Have a history of chronic or recurrent infectious disease or who have or have had a serious infection requiring hospitalization or intravenous antibiotics within the previous 2 months * Have or ever have had a nontuberculous mycobacterial infection or opportunistic infection * Patients known to be infected with human immunodeficiency virus, hepatitis B, or hepatitis C * Have current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease * Patients with a malignancy or who have a history of malignancy (with the exception of certain skin cancers and pre-invasive cervical cancer)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Psoriasis Area-and-severity Index (PASI) 75% Improvement From Baseline at Week 12. | Week 12 | The number of participants achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI) (0 \[best\] - 72 \[worst\]) at Week 12. This is a test of how bad a person's psoriasis is. The combination of redness, scaling, and thickness, as well as overall body involvement determine the PASI score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved a Physician Global Assessment (PGA) Score of Cleared (0) or Minimal (1) at Week 12 | Week 12 | The PGA is used to determine the participant's psoriasis lesions overall at a given time point. Overall lesions will be graded as : (0) = cleared, (1) = minimal, (2) = mild, (3) = moderate, (4) = marked, and (5) = severe for induration, erythema, and scaling. The sum of the 3 scales will be divided by 3 to obtain a final PGA score ranging from 0 \[best\] to 5 \[worst\]. |
| Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | Baseline (Week 0), Week 12 | Change from baseline in Dermatology Life Quality Index (DLQI) from baseline at Week 12. This DLQI is a 10-item questionnaire, that in addition to evaluating overall 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. Scores range from 0 (no impairment in quality of life) to 30 (most impairment in quality of life). |
| Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | Week 52 | The number of participants achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI) (0 \[best\] - 72 \[worst\]) at Week 52 in participants randomly assigned to a treatment group at Week 40. This is a test of how bad a person's psoriasis is. The combination of redness, scaling, and thickness, as well as overall body involvement determine the PASI score. |
Countries
Belgium, Canada, United States
Participant flow
Recruitment details
In this study, 766 patients were randomized in North America and Europe to receive either placebo or ustekinumab (CNTO 1275).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients received placebo at Weeks 0 and 4. At Weeks 12 and 16, placebo crossed over to receive ustekinumab 45 mg or 90 mg. Treatments after Week 16 were dependent on clinical response. | 255 |
| Ustekinumab 45 mg Patients received ustekinumab 45 mg at Weeks 0, 4 and 16. Treatments after Week 16 were dependent on clinical response. At Week 40, patients who achieved PASI 75 at both Week 28 and Week 40 were re-randomized to withdraw from therapy (placebo) or continue 45 mg every 12 week maintenance therapy. | 255 |
| Ustekinumab 90 mg Patients received ustekinumab 90 mg at Week 0, 4 and 16. Treatments after Week 16 were dependent on clinical response. At Week 40, patients who achieved PASI 75 at both Week 28 and Week 40 were re-randomized to withdraw from therapy (placebo) or continue 90 mg every 12 week maintenance therapy. | 256 |
| Total | 766 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| After Controlled Period | Adverse Event | 0 | 0 | 0 | 7 | 8 | 23 | 21 |
| After Controlled Period | Death | 0 | 0 | 0 | 1 | 2 | 0 | 1 |
| After Controlled Period | Lack of Efficacy | 0 | 0 | 0 | 10 | 6 | 28 | 15 |
| After Controlled Period | Lost to Follow-up | 0 | 0 | 0 | 5 | 8 | 9 | 10 |
| After Controlled Period | Other | 0 | 0 | 0 | 13 | 11 | 22 | 25 |
| Controlled Period | Adverse Event | 6 | 0 | 2 | 0 | 0 | 0 | 0 |
| Controlled Period | Lack of Efficacy | 3 | 0 | 1 | 0 | 0 | 0 | 0 |
| Controlled Period | Lost to Follow-up | 1 | 0 | 1 | 0 | 0 | 0 | 0 |
| Controlled Period | Other | 2 | 1 | 6 | 0 | 0 | 0 | 0 |
| Controlled Period | Randomized but not treated | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Ustekinumab 45 mg | Ustekinumab 90 mg | Total |
|---|---|---|---|---|
| Age Continuous | 44.8 Years STANDARD_DEVIATION 11.32 | 44.8 Years STANDARD_DEVIATION 12.48 | 46.2 Years STANDARD_DEVIATION 11.27 | 45.3 Years STANDARD_DEVIATION 11.71 |
| Sex: Female, Male Female | 72 Participants | 80 Participants | 83 Participants | 235 Participants |
| Sex: Female, Male Male | 183 Participants | 175 Participants | 173 Participants | 531 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 | 81 / 255 | 102 / 255 | 84 / 255 | 110 / 123 | 102 / 120 | 207 / 255 | 207 / 251 |
| serious Total, serious adverse events | 2 / 255 | 2 / 255 | 4 / 255 | 20 / 123 | 18 / 120 | 38 / 255 | 33 / 251 |
Outcome results
Primary
Psoriasis Area-and-severity Index (PASI) 75% Improvement From Baseline at Week 12.
The number of participants achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI) (0 \[best\] - 72 \[worst\]) at Week 12. This is a test of how bad a person's psoriasis is. The combination of redness, scaling, and thickness, as well as overall body involvement determine the PASI score.
Time frame: Week 12
Population: Intent to treat. All patients randomized were included in the analysis according to the assigned treatment groups. Patient is considered a non- responder if the patient has used any pre-specified prohibited medications or discontinued due to lack of efficacy, or an AE of worsening of psoriasis, or had missing data at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Psoriasis Area-and-severity Index (PASI) 75% Improvement From Baseline at Week 12. | 8 Participants |
| Ustekinumab 45 mg | Psoriasis Area-and-severity Index (PASI) 75% Improvement From Baseline at Week 12. | 171 Participants |
| Ustekinumab 90 mg | Psoriasis Area-and-severity Index (PASI) 75% Improvement From Baseline at Week 12. | 170 Participants |
p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi square
Comparison: Null Hypothesis: No difference between ustekinumab 90 mg or 45 mg and placebo at an overall significance level of 0.05. Sample Size: With 750 patients (250 in each treatment group), simulation studies were conducted to calculate the power to detect a treatment difference in the primary endpoint between ustekinumab groups and placebo using a CMH test stratified by baseline weight \[\<=90kg vs \> 90 kg). For all the scenarios evaluated, the power is \>99% at an overall significance level of 0.05.p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi square
Secondary
Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12
Change from baseline in Dermatology Life Quality Index (DLQI) from baseline at Week 12. This DLQI is a 10-item questionnaire, that in addition to evaluating overall 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. Scores range from 0 (no impairment in quality of life) to 30 (most impairment in quality of life).
Time frame: Baseline (Week 0), Week 12
Population: Patients were included in the analysis according to the assigned treatment groups. Zero change is imputed if the patient has used any pre-specified prohibited medications or discontinued due to lack of efficacy. Other missing data were not imputed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | 0.0 Scores on a scale |
| Ustekinumab 45 mg | Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | -6.0 Scores on a scale |
| Ustekinumab 90 mg | Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 12 | -7.0 Scores on a scale |
p-value: <0.001ANOVA on van der Waerden normal scores
Comparison: Null Hypothesis: No difference between ustekinumab 90 mg or 45 mg and placebo at an overall significance level of 0.05.p-value: <0.001ANOVA on van der Waerden normal scores
Secondary
Number of Participants Who Achieved a Physician Global Assessment (PGA) Score of Cleared (0) or Minimal (1) at Week 12
The PGA is used to determine the participant's psoriasis lesions overall at a given time point. Overall lesions will be graded as : (0) = cleared, (1) = minimal, (2) = mild, (3) = moderate, (4) = marked, and (5) = severe for induration, erythema, and scaling. The sum of the 3 scales will be divided by 3 to obtain a final PGA score ranging from 0 \[best\] to 5 \[worst\].
Time frame: Week 12
Population: Intent to treat. All patients were included in the analysis according to the assigned treatment groups. Patient is considered a non- responder if the patient has used any pre-specified prohibited medications or discontinued due to lack of efficacy, or an AE of worsening of psoriasis, or had missing data at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Participants Who Achieved a Physician Global Assessment (PGA) Score of Cleared (0) or Minimal (1) at Week 12 | 10 participants |
| Ustekinumab 45 mg | Number of Participants Who Achieved a Physician Global Assessment (PGA) Score of Cleared (0) or Minimal (1) at Week 12 | 151 participants |
| Ustekinumab 90 mg | Number of Participants Who Achieved a Physician Global Assessment (PGA) Score of Cleared (0) or Minimal (1) at Week 12 | 156 participants |
p-value: <0.001Cochran-Mantel-Haenszel(CMH) chi square
Comparison: Null Hypothesis: No difference between ustekinumab 90 mg or 45 mg and placebo at an overall significance level of 0.05.p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi square
Secondary
Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52
The number of participants achieving at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI) (0 \[best\] - 72 \[worst\]) at Week 52 in participants randomly assigned to a treatment group at Week 40. This is a test of how bad a person's psoriasis is. The combination of redness, scaling, and thickness, as well as overall body involvement determine the PASI score.
Time frame: Week 52
Population: Patients were included in the analysis according to the assigned treatment groups. Patient is considered a non- responder if the patient has used any pre-specified prohibited medications or discontinued due to lack of efficacy. Other missing data were not imputed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | 47 participants |
| Ustekinumab 45 mg | Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | 67 participants |
| Ustekinumab 90 mg | Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | 53 participants |
| Group 4: Ustekinumab 90 mg Every 12 Weeks | Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | 77 participants |
| Group 5: Withdrawal Combined Group | Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | 100 participants |
| Group 6: Combined Ustekinumab Every 12 Weeks | Psoriasis Area and Severity Index (PASI) 75 Responders at Week 52 | 144 participants |
p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi square
p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi square
Comparison: Null Hypothesis: No difference between combined maintenance group and the combined withdrawal group, ustekinumab 90 mg maintenance group and the withdrawal group, ustekinumab 45 mg maintenance group and the withdrawal group at an overall significance level of 0.05.p-value: 0.001Cochran-Mantel-Haenszel (CMH) chi square