Psoriasis
Conditions
Keywords
Moderate to Severe Plaque-Type Psoriasis, interleukin 23, IL-12, interleukin-12, interleukin-23, CNTO1275, biologic, Psoriasis, CNTO 1275, IL23, interleukin 12, IL-23, IL12, ustekinumab
Brief summary
The primary objective of this study is to evaluate the efficacy and safety of ustekinumab (CNTO 1275) in the treatment of patients with moderate to severe plaque psoriasis.
Detailed description
Although numerous therapeutic options exist for the treatment of psoriasis, there is still a significant unmet medical need due to the limited effectiveness and/or significant side effect profile of current treatment options. Preclinical studies and early phase clinical studies suggest that interleukins-12 and -23, two molecules that are part of the communication network in the immune system, may play an important role in psoriasis. Ustekinumab (CNTO 1275) is a monoclonal antibody directed against interleukins -12 and -23. This is a randomized (study drug assigned by chance like flipping a coin), double blind (neither physician nor patient knows the name of the assigned drug), parallel-group, multicenter study to determine the effectiveness and safety of two different doses of ustekinumab (CNTO 1275) administered subcutaneously (under the skin) as compared with placebo in patients with moderate to severe plaque-type psoriasis (the most common type of psoriasis). The hypothesis is that ustekinumab (CNTO 1275) will be more effective in treatment of psoriasis than placebo, that the improvement in psoriasis will result in an improved quality of life for treated patients and that ustekinumab (CNTO 1275) will be generally well tolerated. Patients will receive ustekinumab (CNTO 1275), 45 or 90 mg, or placebo administered subcutaneously at weeks 0 and 4 weeks then every 12 weeks thereafter until week 52. For patients who partially respond to the starting regimen, the dosing interval may be adjusted to every 8 weeks. Patients will enter long term extension portion of the study at week 52 during which patients will continue to receive treatment with ustekinumab (CNTO 1275) and will be followed for a total of up to 264 weeks from the initial (week 0) administration of study agent. The dose of ustekinumab (CNTO 1275) will be 45 or 90 mg or placebo administered subcutaneously at weeks 0 and 4 weeks then every 12 weeks thereafter. For patients who partially respond to the starting regimen, the dosing interval may be adjusted to every 8 weeks.
Interventions
DRUGPlacebo; Ustekinumab (CNTO 1275) 45 or 90 mg
Placebo at Weeks 0 and 4 and blinded SC injections of ustekinumab, 45 or 90 mg, at Weeks 12 and 16; followed by a dosing regimen to be determined by patient's response status for Weeks 28 to 52; followed by unblinded dosing that may be adjusted at the investigator's discretion for Weeks 52 to 264
DRUGUstekinumab (CNTO 1275) 45 mg
Ustekinumab, 45 mg, at Weeks 0 and 4 and every 12 weeks for Weeks 16 to 28. Followed by a dosing regimen to be determined by patient's response status for Weeks 28 to 52; followed by unblinded dosing that may be adjusted at the investigator's discretion for Weeks 52 to 264
DRUGUstekinumab (CNTO 1275) 90 mg
Ustekinumab, 90 mg, at Weeks 0 and 4 and every 12 weeks for Weeks 16 to 28. Followed by a dosing regimen to be determined by patient's response status for Weeks 28 to 52; followed by unblinded dosing that may be adjusted at the investigator's discretion for Weeks 52 to 264
Sponsors
Centocor Research & Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Plaque-type psoriasis diagnosed \>= 6 months prior * Plaque-type psoriasis covering at least 10% of total body surface areas * Psoriasis area-and-severity index score of \>=12 at screening and baseline * Considered by treating dermatologist to be a candidate for phototherapy or systemic treatment of psoriasis * Women of childbearing potential and all men must agree to use adequate birth control measures throughout the trials and for 12 months following the last injection of study agent * Have no history of latent or active tuberculosis (TB)
Exclusion criteria
* Currently have nonplaque forms of psoriasis or drug-induced psoriasis * Women who are pregnant or nursing, or men and women planning pregnancy while enrolled in the study * Patients who have used any therapeutic agent targeted at reducing IL-12 or IL-23 * Patients who have had a Bacillus Calmette-Guerin (BCG) vaccination within the previous 12 months prior to screening * Patients who 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 prior to screening * Patients who have or ever have had a nontuberculous mycobacterial infection or opportunistic infection * Patients known to be infected with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C * Patients who 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) * Patients participating in another trial using an investigational agent or procedure * Systemic immunosuppressants within 4 weeks of the first administration of study agent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent or Above at Week 12 | Week 0 to Week 12 | Number of participants achieving greater than or equal to 75 percent improvement in PASI at Week 12. PASI is a widely used tool for the measurement of severity of psoriasis. This is a test of how bad a person's psoriasis is. The scale combines redness, scaling, and thickness, as well as overall body involvement to determine the PASI score. The scale ranges from 0 (best) to 72 (worst). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Physician Global Assessment (PGA) of Cleared or Minimal at Week 12 | Week 12 | Number of participants achieving a physician global assessment (PGA) (0 \[none\] to 5 \[severe\]) of cleared or minimal at Week 12. The PGA is 7-point scale used in clinical trials of various diseases. In this the physician checks the state of the disease and gives them score from 0 (clear) to 5 (severe). |
| Change in Dermatology Life Quality Index (DLQI) at Week 12 | Baseline to Week 12 | Change in Dermatology Life Quality Index (DLQI) from baseline at Week 12. The 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). |
| Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | Week 40 to Week 52 | Number of visits at which participants randomized at Week 28 achieved at least 75 percent improvement from baseline in PASI from Week 40 through Week 52 in participants randomized at Week 28. PASI is a widely used tool for the measurement of severity of psoriasis. This is a test of how bad a person's psoriasis is. The scale combines redness, scaling, and thickness, as well as overall body involvement to determine the PASI score. The scale ranges from 0 (best) to 72 (worst). |
Countries
Austria, Canada, France, Germany, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
In this trial, 1230 participants were randomized to either placebo or ustekinumab (CNTO 1275). There were 70 sites in North America and Europe.
Pre-assignment details
2 participants from placebo group (in controlled period \[CP\]) after completing the CP did not crossover to the Placebo -\> Ustekinumab 90 mg (after CP) treatment group and they are not included in this group (after CP). Thus, 1199 participants completed the 1st period (CP); however, only 1197 participants started the 2nd period (after CP).
Participants by arm
| Arm | Count |
|---|---|
| Group I: Placebo Placebo participants 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. | 410 |
| Group II: Ustekinumab 45 mg Participants received ustekinumab 45 mg at Weeks 0, 4 and 16. Treatments after Week 16 were dependent on clinical response. At Week 28, participants who achieved a greater than and equal to 50 percentage but less than 75 percentage improvement in PASI were re-randomized to continue 45 mg every 12 week or dose adjust to 45 mg every 8 week dosing. | 409 |
| Group III: Ustekinumab 90 mg Participants received ustekinumab 90 mg at Weeks 0, 4 and 16. Treatments after Week 16 were dependent on clinical response. At Week 28, participants who achieved a greater than and equal 50 percentage but less than 75 percentage improvement in PASI were re-randomized to continue 90 mg every 12 week or dose adjust to 90 mg every 8 week dosing. | 411 |
| Total | 1,230 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| After Controlled Period | Adverse Event | 0 | 0 | 0 | 18 | 16 | 31 | 40 |
| After Controlled Period | Death | 0 | 0 | 0 | 3 | 1 | 1 | 3 |
| After Controlled Period | Lack of Efficacy | 0 | 0 | 0 | 15 | 17 | 37 | 24 |
| After Controlled Period | Lost to Follow-up | 0 | 0 | 0 | 7 | 12 | 13 | 18 |
| After Controlled Period | Other | 0 | 0 | 0 | 15 | 9 | 40 | 28 |
| Controlled Period | Adverse Event | 7 | 2 | 5 | 0 | 0 | 0 | 0 |
| Controlled Period | Death | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Controlled Period | Lack of Efficacy | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Controlled Period | Lost to Follow-up | 2 | 3 | 0 | 0 | 0 | 0 | 0 |
| Controlled Period | Other | 5 | 1 | 3 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group I: Placebo | Group II: Ustekinumab 45 mg | Group III: Ustekinumab 90 mg | Total |
|---|---|---|---|---|
| Age Continuous | 47.0 years STANDARD_DEVIATION 12.47 | 45.1 years STANDARD_DEVIATION 12.06 | 46.6 years STANDARD_DEVIATION 12.14 | 46.2 years STANDARD_DEVIATION 12.24 |
| Sex: Female, Male Female | 127 Participants | 126 Participants | 137 Participants | 390 Participants |
| Sex: Female, Male Male | 283 Participants | 283 Participants | 274 Participants | 840 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 | 116 / 410 | 119 / 409 | 114 / 411 | 168 / 197 | 159 / 195 | 342 / 407 | 343 / 409 |
| serious Total, serious adverse events | 8 / 410 | 8 / 409 | 5 / 411 | 40 / 197 | 41 / 195 | 81 / 407 | 73 / 409 |
Outcome results
Primary
Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent or Above at Week 12
Number of participants achieving greater than or equal to 75 percent improvement in PASI at Week 12. PASI is a widely used tool for the measurement of severity of psoriasis. This is a test of how bad a person's psoriasis is. The scale combines redness, scaling, and thickness, as well as overall body involvement to determine the PASI score. The scale ranges from 0 (best) to 72 (worst).
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 had missing data at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent or Above at Week 12 | 15 Participants |
| Group II: Ustekinumab 45 mg | Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent or Above at Week 12 | 273 Participants |
| Group III: Ustekinumab 90 mg | Number of Participants With Psoriasis Area and Severity Index (PASI) Score of 75 Percent or Above at Week 12 | 311 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 1200 participants (400 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 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, 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 to Week 12
Population: Participants were included in the analysis according to the assigned treatment groups. Zero change is imputed if the partcipant 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 | -0.5 Units on a scale |
| Group II: Ustekinumab 45 mg | Change in Dermatology Life Quality Index (DLQI) at Week 12 | -8.0 Units on a scale |
| Group III: Ustekinumab 90 mg | Change in Dermatology Life Quality Index (DLQI) at Week 12 | -9.0 Units 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 Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52
Number of visits at which participants randomized at Week 28 achieved at least 75 percent improvement from baseline in PASI from Week 40 through Week 52 in participants randomized at Week 28. PASI is a widely used tool for the measurement of severity of psoriasis. This is a test of how bad a person's psoriasis is. The scale combines redness, scaling, and thickness, as well as overall body involvement to determine the PASI score. The scale ranges from 0 (best) to 72 (worst).
Time frame: Week 40 to Week 52
Population: All participants randomized at Week 28 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Placebo | Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | 0 Participants |
| Group II: Ustekinumab 45 mg | Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | 1 Participants |
| Group III: Ustekinumab 90 mg | Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | 3 Participants |
| Group 4: Ustekinumab 90 mg Every 12 Weeks | Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | 1 Participants |
| Group 5: Combined (8 Week Dosing) | Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | 2 Participants |
| Group 6: Combined (12 Week Dosing) | Number of Participants Visits With Psoriasis Area and Severity Index (PASI) 75 From Week 40 Through Week 52 | 1 Participants |
p-value: 0.468Cochran-Mantel-Haenszel (row mean score)
p-value: 0.21Cochran-Mantel-Haenszel (row mean score)
Comparison: Null Hypothesis: No difference between combined q8 group and the combined q12 group, 45 mg q8 and 45 mg q12, 90 mg q8 and 90 mg q12 at an overall significance level of 0.05.p-value: 0.014Cochran-Mantel-Haenszel (row mean score)
Secondary
Number of Participants With Physician Global Assessment (PGA) of Cleared or Minimal at Week 12
Number of participants achieving a physician global assessment (PGA) (0 \[none\] to 5 \[severe\]) of cleared or minimal at Week 12. The PGA is 7-point scale used in clinical trials of various diseases. In this the physician checks the state of the disease and gives them score from 0 (clear) to 5 (severe).
Time frame: Week 12
Population: Intent to treat. All participants 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 had missing data at Week 12.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Placebo | Number of Participants With Physician Global Assessment (PGA) of Cleared or Minimal at Week 12 | 18 Participants |
| Group II: Ustekinumab 45 mg | Number of Participants With Physician Global Assessment (PGA) of Cleared or Minimal at Week 12 | 277 Participants |
| Group III: Ustekinumab 90 mg | Number of Participants With Physician Global Assessment (PGA) of Cleared or Minimal at Week 12 | 300 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 significancd level of 0.05.p-value: <0.001Cochran-Mantel-Haenszel (CMH) chi square