Psoriasis
Conditions
Keywords
psoriasis, Ustekinumab, Stelara, Etanercept, Enbrel
Brief summary
This is a two-part study. The purpose of the pilot study (Part 1) is to optimize the acquisition, handling and shipping procedure for skin biopsies obtained from participants with plaque psoriasis. No treatment will be administered. Part 2 will include 2 cohorts. In Cohort 1, the effects of 16 weeks of treatment with either ustekinumab or etanercept on biomarkers in lesional skin in participants with moderate to severe psoriasis will be evaluated. In Cohort 2, biomarkers of lesional skin from participants with moderate to severe psoriasis who are not treated with biologic therapy will be evaluated over 16 weeks. The primary hypothesis is that treatment with ustekinumab reduces messenger RNA (mRNA) expression of genes in the interleukin 12 (IL-12) pathway that are modulated by interferon gamma (IFN-γ).
Interventions
DRUGUstekinumab
Ustekinumab 45 mg per dose, administered subcutaneously for participants weighing ≤ 100 kg, and ustekinumab 90 mg per dose administered subcutaneously for participants weighing \> 100 kg on Day 1, and Weeks 4 and 16
DRUGEtanercept
Etanercept 50 mg twice weekly by self-administered subcutaneous injection for 12 weeks, then once weekly for 4 weeks
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Is unlikely to conceive (for female participants of reproductive potential)- Part 2 * Has a diagnosis of predominantly plaque psoriasis for ≥ 6 months-Parts 1 and 2 * Has a plaque-type psoriatic lesion with a Target Lesion Score (TLS) score of ≥ 6 in a hidden area of the body such as the abdomen, thighs, lower back or buttock that is suitable for biopsy- Part 1 * Is considered to be a candidate for phototherapy or systemic therapy - Part 2 * Has a Psoriasis Area and Severity Index (PASI) score ≥ 12 at Baseline - Part 2 * Has psoriasis body surface area (BSA) involvement ≥ 10% at Baseline - Part 2 * Has a Physician's Global Assessment (PGA) of at least moderate disease (moderate, marked, or severe) at Baseline - Part 2 * Is considered to be eligible according to the tuberculosis (TB) screening criteria - Part 2
Exclusion criteria
* Has nonplaque forms of psoriasis specifically erythrodermic psoriasis, predominantly pustular psoriasis, medication-induced or medication-exacerbated psoriasis, or new onset guttate psoriasis - Parts 1 and 2 * Women of childbearing potential who are pregnant, intend to become pregnant (within 6 months of completing the trial), or are lactating - Parts 1 and 2 * Has a history of neoplastic disease or concurrent malignancy - Part 2 * Requires oral or injectable corticosteroids during the trial - Part 2 * Have any infection requiring treatment with antibiotics within 2 weeks prior to screening or serious infection requiring hospitalization or treatment with IV antibiotics within 8 weeks prior to screening - Part 2 * Has a positive human immunodeficiency virus (HIV) test result, hepatitis B surface antigen, or hepatitis C test result - Part 2 * Has received live virus vaccination within 4 weeks prior to screening or who intends to receive live virus vaccination during the trial - Part 2 * Has previous exposure to any agents targeting IL-12 and/or IL-23 (e.g. ustekinumab) - Part 2 * Has prior exposure tumor necrosis factor (TNF) antagonists (e.g. infliximab, etanercept, golimumab, adalimumab) and discontinued due to lack of efficacy or for adverse effects - Part 2 * Has been treated with any medications that are associated with Progressive Multifocal Leukoencephalopathy (PML), such as efalizumab (Raptiva) or natalizumab (Tysabri) - Part 2 * Has taken any immunosuppressive agents (e.g. corticosteroids, methotrexate, azathioprine, cyclosporine) for treatment of conditions other than for Psoriasis within 4 weeks of screening - Part 2 * Is currently taking any of the prohibited medications and is unwilling to washout of the medication(s) for the indicated timeframe prior to screening and for the duration of the study - Part 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Composite Gene Expression Score Based on IL-12 Pathway Related Interferon Gamma (IFN-γ)-Modulated Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Baseline and Weeks 1, 2, 4, and 16 | Skin biopsies were collected from participants at baseline and after treatment with ustekinumab for 1,2,4 and 16 weeks. The expression of messenger RNA (mRNA) from three pre-defined IL-12 pathway related genes, modulated by interferon gamma (IFN-γ), namely IFN-γ, inducible nitric oxide synthase(iNOS) and CXC motif chemokine 10(CXCL10) was quantitated by real-time polymerase chain reaction (qPCR), with the data normalized by the delta-delta Ct method. The expression score for each gene, showing the percentage difference from baseline, was calculated as follows : \[(baseline - post baseline)/baseline\] x 100. Composite gene expression scores were derived for each individual by summing the expression scores of the individual genes. Positive composite scores denote a decrease from baseline in gene expression. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Composite Gene Expression Score Based on Interleukin 23 (IL-23) Pathway Related Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Baseline and Weeks 1, 2, 4, and 16 | Skin biopsies were collected from participants at baseline and after treatment with ustekinumab for 1,2,4 and 16 weeks. The mRNA expression of eight pre-defined IL-23 pathway related genes, namely beta 4 defensin (DEFB4), CXC motif chemokine 8 (CXCL8), Interleukins 17A, 17F, 20, 22, 23A (IL-17, IL-17F, IL-20, IL-22, IL-23A) and cyclic AMP dependent protein kinase (CAMP) was quantitated by qPCR, with the data normalized by the delta-delta Ct method. The expression score for each gene, showing the percentage difference from baseline, was calculated as follows : \[(baseline - post baseline)/baseline\] x 100. Composite gene expression scores were derived for each individual by summing the expression scores of the individual genes. Positive composite scores denote a reduction from baseline in gene expression. |
| Change From Baseline in Gene Expression Score for Interleukin 17 (IL-17) in Psoriatic Lesions of Participants Treated With Etanercept | Baseline and Weeks 1, 2, 4, and 16 | Participants had skin biopsies performed at baseline and after treatment with etanercept for 1,2,4 and 16 weeks. The expression of IL-17 mRNA was quantitated by qPCR, with the data normalized by the delta-delta Ct method. The expression score, showing the percentage difference from baseline, was calculated as follows : \[(baseline - post baseline)/baseline\] x 100. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Etanercept Etanercept : Etanercept 50 mg twice weekly by self-administered subcutaneous injection for 12 weeks, then once weekly for 4 weeks | 10 |
| No Treatment No treatment administered | 10 |
| Ustekinumab Ustekinumab : Ustekinumab 45 mg per dose, administered subcutaneously for participants weighing ≤ 100 kg, and ustekinumab 90 mg per dose administered subcutaneously for participants weighing \> 100 kg on Day 1, and Weeks 4 and 16 | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Etanercept | No Treatment | Ustekinumab | Total |
|---|---|---|---|---|
| Age, Continuous | 39.5 years STANDARD_DEVIATION 12.5 | 53.4 years STANDARD_DEVIATION 13 | 45.7 years STANDARD_DEVIATION 12.1 | 46.1 years STANDARD_DEVIATION 13.1 |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 7 Participants | 12 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 13 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 10 | 2 / 10 | 6 / 20 |
| serious Total, serious adverse events | 1 / 10 | 0 / 10 | 0 / 20 |
Outcome results
Primary
Change From Baseline in Composite Gene Expression Score Based on IL-12 Pathway Related Interferon Gamma (IFN-γ)-Modulated Genes in Psoriatic Lesions of Participants Treated With Ustekinumab
Skin biopsies were collected from participants at baseline and after treatment with ustekinumab for 1,2,4 and 16 weeks. The expression of messenger RNA (mRNA) from three pre-defined IL-12 pathway related genes, modulated by interferon gamma (IFN-γ), namely IFN-γ, inducible nitric oxide synthase(iNOS) and CXC motif chemokine 10(CXCL10) was quantitated by real-time polymerase chain reaction (qPCR), with the data normalized by the delta-delta Ct method. The expression score for each gene, showing the percentage difference from baseline, was calculated as follows : \[(baseline - post baseline)/baseline\] x 100. Composite gene expression scores were derived for each individual by summing the expression scores of the individual genes. Positive composite scores denote a decrease from baseline in gene expression.
Time frame: Baseline and Weeks 1, 2, 4, and 16
Population: Pre-specified to be collected only in participants treated with Ustekinumab. One participant treated with Ustekinumab with extreme outlying data, likely due to mislabeling of lesional and nonlesional tissues, was excluded from the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on IL-12 Pathway Related Interferon Gamma (IFN-γ)-Modulated Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 1 | 53.68 Gene expression score |
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on IL-12 Pathway Related Interferon Gamma (IFN-γ)-Modulated Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 2 | 130.54 Gene expression score |
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on IL-12 Pathway Related Interferon Gamma (IFN-γ)-Modulated Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 4 | 180.19 Gene expression score |
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on IL-12 Pathway Related Interferon Gamma (IFN-γ)-Modulated Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 16 | 240.29 Gene expression score |
Comparison: Week 1p-value: 0.016Wilcoxon (Mann-Whitney)
Comparison: Week 2p-value: 0.007Wilcoxon (Mann-Whitney)
Comparison: Week 4p-value: 0.00015Wilcoxon (Mann-Whitney)
Comparison: Week 16p-value: 0.000184Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Composite Gene Expression Score Based on Interleukin 23 (IL-23) Pathway Related Genes in Psoriatic Lesions of Participants Treated With Ustekinumab
Skin biopsies were collected from participants at baseline and after treatment with ustekinumab for 1,2,4 and 16 weeks. The mRNA expression of eight pre-defined IL-23 pathway related genes, namely beta 4 defensin (DEFB4), CXC motif chemokine 8 (CXCL8), Interleukins 17A, 17F, 20, 22, 23A (IL-17, IL-17F, IL-20, IL-22, IL-23A) and cyclic AMP dependent protein kinase (CAMP) was quantitated by qPCR, with the data normalized by the delta-delta Ct method. The expression score for each gene, showing the percentage difference from baseline, was calculated as follows : \[(baseline - post baseline)/baseline\] x 100. Composite gene expression scores were derived for each individual by summing the expression scores of the individual genes. Positive composite scores denote a reduction from baseline in gene expression.
Time frame: Baseline and Weeks 1, 2, 4, and 16
Population: Pre-specified to be collected only in participants treated with Ustekinumab. One participant treated with Ustekinumab with extreme outlying data, likely due to mislabeling of lesional and nonlesional tissues, was excluded from the analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on Interleukin 23 (IL-23) Pathway Related Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 1 | 44.24 Gene expression score |
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on Interleukin 23 (IL-23) Pathway Related Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 2 | 399.31 Gene expression score |
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on Interleukin 23 (IL-23) Pathway Related Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 4 | 412.79 Gene expression score |
| Ustekinumab | Change From Baseline in Composite Gene Expression Score Based on Interleukin 23 (IL-23) Pathway Related Genes in Psoriatic Lesions of Participants Treated With Ustekinumab | Week 16 | 716.14 Gene expression score |
Comparison: Week 1p-value: 0.397Wilcoxon (Mann-Whitney)
Comparison: Week 2p-value: 0.01Wilcoxon (Mann-Whitney)
Comparison: Week 4p-value: 0.002Wilcoxon (Mann-Whitney)
Comparison: Week 16p-value: 0.000215Wilcoxon (Mann-Whitney)
Secondary
Change From Baseline in Gene Expression Score for Interleukin 17 (IL-17) in Psoriatic Lesions of Participants Treated With Etanercept
Participants had skin biopsies performed at baseline and after treatment with etanercept for 1,2,4 and 16 weeks. The expression of IL-17 mRNA was quantitated by qPCR, with the data normalized by the delta-delta Ct method. The expression score, showing the percentage difference from baseline, was calculated as follows : \[(baseline - post baseline)/baseline\] x 100.
Time frame: Baseline and Weeks 1, 2, 4, and 16
Population: Pre-specified to be collected only in participants treated with Etanercept.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Ustekinumab | Change From Baseline in Gene Expression Score for Interleukin 17 (IL-17) in Psoriatic Lesions of Participants Treated With Etanercept | Week 1 | 5.17 Gene expression score |
| Ustekinumab | Change From Baseline in Gene Expression Score for Interleukin 17 (IL-17) in Psoriatic Lesions of Participants Treated With Etanercept | Week 2 | 17.75 Gene expression score |
| Ustekinumab | Change From Baseline in Gene Expression Score for Interleukin 17 (IL-17) in Psoriatic Lesions of Participants Treated With Etanercept | Week 4 | 65.50 Gene expression score |
| Ustekinumab | Change From Baseline in Gene Expression Score for Interleukin 17 (IL-17) in Psoriatic Lesions of Participants Treated With Etanercept | Week 16 | 52.77 Gene expression score |
Comparison: Week 1p-value: 0.787Wilcoxon (Mann-Whitney)
Comparison: Week 2p-value: 0.577Wilcoxon (Mann-Whitney)
Comparison: Week 4p-value: 0.053Wilcoxon (Mann-Whitney)
Comparison: Week 16p-value: 0.098Wilcoxon (Mann-Whitney)