Psoriasis
Conditions
Keywords
Psoriasis, ENBREL, etanercept, anti-TNF
Brief summary
The purpose of this study is to determine the relationship between two types of cell signals, type I interferon (IFN) and tumor necrosis factor (TNF), in psoriatic skin prior to and during treatment with etanercept and correlate that information with the degree of the improvement in the psoriasis.
Detailed description
Hypothesis: The balance between type I IFN and TNF determines the response to anti-TNF treatment. The goal of the proposed study is to address this hypothesis and demonstrate that the strength of the type I IFN signature in psoriatic skin is the major determinant of the clinical response to anti-TNF treatment. Purpose: Determine the strength of the type I interferon and TNF signal in psoriatic skin prior to and during treatment with etanercept and correlate with degree of clinical improvement. Study Population: up to 50 subjects, men or women over the age of 18 with clinically stable plaque psoriasis, who meet the wash out requirements and other exclusion criteria Psoriatic patients will receive 100 mg etanercept per week (2 separate single-use pre-filled 50 mg subcutaneous injections taken on two separate days) for 3 months. Procedures: Urine pregnancy test, TB test, photography, Physical Examinations, Skin Examinations, Study Drug, Peripheral blood and biopsies Anticipated Results: We expect that patients with strong IFN-α signature in psoriatic skin along with weak TNF-α signature will have minimal response to anti-TNF treatment, while patients with the opposite pattern, weak IFN and strong TNF signature, will have significant clinical improvement.
Interventions
DRUGetanercept
100 mg Etanercept injections per week (2 separate single-use pre-filled 50 mg subcutaneous injections taken on two separate days) for 3 months
Sponsors
Amgen
University of Michigan
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* At least 18 years of age at screening. * Clinically stable moderate to severe plaque psoriasis at screening and baseline. * Subject must be: * A man or * A woman who is surgically sterile or at least 3 years postmenopausal or * A woman of childbearing potential who has had a negative pregnancy test within 7 days before the first dose of study drug. * If the subject is sexually active, (s)he must agree to use a medically acceptable form of contraception during screening and throughout the study.
Exclusion criteria
* Grade 3 or 4 adverse events or infections within 28 days before screening, or between the screening visit and drug initiation. * Active or chronic infection within 4 weeks before screening visit, or between the screening and baseline visits. * Evidence of skin conditions other than psoriasis that would interfere with the evaluations of the effect of study medication on psoriasis. * Use of oral psoralen with ultraviolet A (PUVA), oral retinoids, cyclosporine, alefacept, or any other systemic anti-psoriasis therapy within 28 days study drug initiation. * Use of ulltraviolet B (UVB) therapy, topical steroids at no higher than moderate strength, topical vitamin A or D analog preparations, or anthralin with 14 days of study initiation. * Prior or concurrent use of cyclophosphamide therapy * Concurrent sulfasalazine therapy. * Known hypersensitivity to Enbrel® (etanercept) or any of its components or known to have antibodies to etanercept. * Current enrollment in any other investigational device or investigational drug trial(s), or receipt of any other investigational agent(s) within 28 days before baseline visit. * Use of any biologic drugs within 28 days of study drug initiation. * Concurrent use of Anakinra. * Severe comorbidities (diabetes mellitus requiring insulin; congestive heart failure (CHF) of any severity or myocardial infarction or cerebrovascular accident or transient ischemic attack within 3 months of screening visit; unstable angina pectoris, uncontrolled hypertension (sitting systolic blood pressure (BP) \<80 mm Hg or \> 160 or diastolic BP \> 100 mm Hg), oxygen-dependent severe pulmonary disease, history of cancer within 5 years (other than resected cutaneous basal or squamous cell carcinoma of the skin or in situ cervical cancer) * Known history of tuberculosis (TB), or previous positive purified protein derivative (PPD) test. Any mycobacterial disease or high risk factors for tuberculosis (TB), such as family member with TB, positive purified protein derivative (PPD) or taking anti-tuberculosis medication. * Known HIV-positive status or known history of any other immuno-suppressing disease. * Concurrent or history of psychiatric disease that would interfere with ability to comply with study protocol or give informed consent. * History of alcohol or drug abuse within 12 months of screening visit. * Latex sensitivity \[Nota Bene: only applicable if they are using prefilled syringe or prefilled SureClick™ autoinjector presentations\] * Exposure to hepatitis B or hepatitis C or to high risk factors for hepatitis B or C, such as intravenous drug use in patient. * Systemic lupus erythematosus, history of multiple sclerosis, transverse myelitis, optic neuritis or seizure disorder. * Use of a live vaccine 90 days prior to screening visit, or concurrent use of a live vaccine. * Any condition or circumstances judged by the patient's physician\[or the investigator or medically qualified study staff\] to render this clinical trial detrimental or otherwise unsuitable for the patient's participation. * History of non-compliance with other therapies. * Pregnant or nursing females. * Diagnosis of multiple sclerosis in first degree family relationship (parent, sibling or child)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Psoriasis Area and Severity Index (PASI) Score | Baseline, 12 weeks | A cumulative change in PASI score from baseline to week 12 will be calculated for each patient. The PASI is the industry standard to decrease/eliminate subjectivity in determining psoriasis severity. It is a quantitative rating scale for measuring the severity of psoriatic lesions based on area coverage and plaque appearance. The severity of plaque characteristics (erythema, thickness and scaling) for body regions (head, upper limbs, trunk and lower limbs) is combined with the degree of plaque involvement in each body region to determine a single PASI score in the range of 0 (no disease) and 72 (maximal disease). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Necrosis Factor (TNF)-Alpha Signal Strength | Baseline, Week 6, Week 12 | Strength of TNF-alpha signatures will be measured in skin of study subjects at initiation, during and after treatment. The strength of these signals will be done using bioinformatic approach quantifying transcriptional signature of these cytokines. The strength of the cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. PASI response profile will be categorized according to improvement in PASI score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline). |
| Interferon (IFN)-Alpha Signal Strength | Baseline, Week 6, Week 12 | Strength of IFN-alpha signatures will be measured in skin of study subjects at initiation, during and after treatment. The strength of these signals in skin will be done using bioinformatic approach quantifying transcriptional signature of these cytokines. The strength of the cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. PASI response profile will be categorized according to improvement in PASI score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline). |
| Psoriasis Area and Severity Index (PASI) Response Profile | 12 Weeks | Subjects will be categorized according to improvement in Psoriasis Area and Severity Index (PASI) score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Etanercept 100 mg Etanercept injections per week for 3 months.
etanercept: 100 mg Etanercept injections per week (2 separate single-use pre-filled 50 mg subcutaneous injections taken on two separate days) for 3 months | 46 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Etanercept |
|---|---|
| Age, Continuous | 40.83 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Interferon (IFN)-alpha Signal | 2118.20 rpkm |
| Psoriasis Area and Severity Index (PASI) Score | 14.16 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 44 Participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 29 Participants |
| Tumor Necrosis Factor (TNF)-alpha Signal | 111.33 rpkm |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 46 |
| other Total, other adverse events | 9 / 46 |
| serious Total, serious adverse events | 1 / 46 |
Outcome results
Primary
Change in Psoriasis Area and Severity Index (PASI) Score
A cumulative change in PASI score from baseline to week 12 will be calculated for each patient. The PASI is the industry standard to decrease/eliminate subjectivity in determining psoriasis severity. It is a quantitative rating scale for measuring the severity of psoriatic lesions based on area coverage and plaque appearance. The severity of plaque characteristics (erythema, thickness and scaling) for body regions (head, upper limbs, trunk and lower limbs) is combined with the degree of plaque involvement in each body region to determine a single PASI score in the range of 0 (no disease) and 72 (maximal disease).
Time frame: Baseline, 12 weeks
Population: Only those subjects who finished the study (have a Week 0 and Week 12 visit with recorded PASI) are included in the analysis assessing a change from baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PASI Score at Week 0 | Change in Psoriasis Area and Severity Index (PASI) Score | 13.92 units on a scale | Standard Error 1.11 |
| PASI Score at Week 12 | Change in Psoriasis Area and Severity Index (PASI) Score | 4.43 units on a scale | Standard Error 0.48 |
Comparison: A cumulative score reflecting change in PASI during the course of treatment was calculated and treated as a continuous response variable. Linear modeling was done to determine if change in PASI score was associated with the baseline TNF-alpha signal, baseline IFN-alpha signal and/or an interaction between these two signals.p-value: 0.38Regression, Linear
Secondary
Interferon (IFN)-Alpha Signal Strength
Strength of IFN-alpha signatures will be measured in skin of study subjects at initiation, during and after treatment. The strength of these signals in skin will be done using bioinformatic approach quantifying transcriptional signature of these cytokines. The strength of the cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. PASI response profile will be categorized according to improvement in PASI score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline).
Time frame: Baseline, Week 6, Week 12
Population: PASI response profile is only done for those subjects who completed the study, n=42. Biopsy not completed on one subject at baseline. Tissue not able to be processed for two subjects at baseline, Week 6 and Week 12. Biopsy not completed on three subjects at Week 6 visit. Biopsy not completed on three different subjects at Week 12 visit.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| PASI Score at Week 0 | Interferon (IFN)-Alpha Signal Strength | PASI Responder | 2082.72 rpkm | Standard Error 70.73 |
| PASI Score at Week 0 | Interferon (IFN)-Alpha Signal Strength | PASI Intermediate-Responder | 2106.72 rpkm | Standard Error 57.75 |
| PASI Score at Week 0 | Interferon (IFN)-Alpha Signal Strength | PASI Non-Responder | 2102.64 rpkm | Standard Error 141.46 |
| PASI Score at Week 12 | Interferon (IFN)-Alpha Signal Strength | PASI Non-Responder | 2035.94 rpkm | Standard Error 168.36 |
| PASI Score at Week 12 | Interferon (IFN)-Alpha Signal Strength | PASI Responder | 2146.83 rpkm | Standard Error 84.18 |
| PASI Score at Week 12 | Interferon (IFN)-Alpha Signal Strength | PASI Intermediate-Responder | 2186.17 rpkm | Standard Error 68.73 |
| TNF-alpha Signal Strength at Week 12 | Interferon (IFN)-Alpha Signal Strength | PASI Responder | 2180.36 rpkm | Standard Error 88.46 |
| TNF-alpha Signal Strength at Week 12 | Interferon (IFN)-Alpha Signal Strength | PASI Intermediate-Responder | 2107.22 rpkm | Standard Error 72.23 |
| TNF-alpha Signal Strength at Week 12 | Interferon (IFN)-Alpha Signal Strength | PASI Non-Responder | 1923.33 rpkm | Standard Error 176.92 |
Comparison: The strength of the IFN-alpha cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. Testing if IFN-alpha signals are significantly altered during the course of etanercept therapy and if such changes differ between subjects with different PASI response profiles.p-value: 0.34ANOVA
Secondary
Psoriasis Area and Severity Index (PASI) Response Profile
Subjects will be categorized according to improvement in Psoriasis Area and Severity Index (PASI) score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline).
Time frame: 12 Weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PASI Score at Week 0 | Psoriasis Area and Severity Index (PASI) Response Profile | Responders | 19 Participants |
| PASI Score at Week 0 | Psoriasis Area and Severity Index (PASI) Response Profile | Intermediate Responders | 20 Participants |
| PASI Score at Week 0 | Psoriasis Area and Severity Index (PASI) Response Profile | Non-Responders | 3 Participants |
Secondary
Tumor Necrosis Factor (TNF)-Alpha Signal Strength
Strength of TNF-alpha signatures will be measured in skin of study subjects at initiation, during and after treatment. The strength of these signals will be done using bioinformatic approach quantifying transcriptional signature of these cytokines. The strength of the cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. PASI response profile will be categorized according to improvement in PASI score: responders (greater than 75% reduction in PASI from baseline), intermediate-responders (those with greater than 25% and less than 75% reduction in PASI from baseline), and non-responders (less than 25% reduction in PASI from baseline).
Time frame: Baseline, Week 6, Week 12
Population: PASI response profile is only done for those subjects who completed the study, n=42. Biopsy not completed on one subject at baseline. Tissue not able to be processed for two subjects at baseline, Week 6 and Week 12. Biopsy not completed on three subjects at Week 6 visit. Biopsy not completed on three different subjects at Week 12 visit.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| PASI Score at Week 0 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Intermediate-Responder | 107.79 rpkm | Standard Error 6.04 |
| PASI Score at Week 0 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Non-Responder | 110.62 rpkm | Standard Error 14.79 |
| PASI Score at Week 0 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Responder | 98.26 rpkm | Standard Error 7.4 |
| PASI Score at Week 12 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Non-Responder | 103.68 rpkm | Standard Error 20.67 |
| PASI Score at Week 12 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Responder | 85.82 rpkm | Standard Error 10.34 |
| PASI Score at Week 12 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Intermediate-Responder | 108.02 rpkm | Standard Error 8.44 |
| TNF-alpha Signal Strength at Week 12 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Intermediate-Responder | 92.01 rpkm | Standard Error 7.34 |
| TNF-alpha Signal Strength at Week 12 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Responder | 64.157 rpkm | Standard Error 8.99 |
| TNF-alpha Signal Strength at Week 12 | Tumor Necrosis Factor (TNF)-Alpha Signal Strength | PASI Non-Responder | 123.08 rpkm | Standard Error 17.98 |
Comparison: The strength of the TNF-alpha cytokine signals will be treated as a response variable in a univariate repeated measure analysis of variance, with PASI response profile and time as covariates. Testing if TNF-alpha signals are significantly altered during the course of etanercept therapy and if such changes differ between subjects with different PASI response profiles.p-value: 0.03ANOVA