A Study in Participants With Moderate to Severe Psoriasis (UNCOVER-3)

Study Overview
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Brief Summary
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This study will assess the safety and efficacy of ixekizumab (LY2439821), compared to etanercept and placebo in participants with moderate to severe chronic plaque psoriasis.

Official Title
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A 12-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Comparing the Efficacy and Safety of LY2439821 to Etanercept and Placebo in Patients With Moderate to Severe Plaque Psoriasis With a Long-Term Extension Period

Conditions
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Psoriasis

Intervention / Treatment
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* Drug: Placebo
* Drug: 50 mg etanercept
* Drug: 80 mg ixekizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presents with chronic plaque psoriasis based on a confirmed diagnosis of chronic psoriasis for at least 6 months prior to randomization At least 10% Body Surface Area (BSA) of Psoriasis at screening and at randomization Static Physician Global Assessment (sPGA) score of at least 3 and Psoriasis Area and Severity Index (PASI) score of at least 12 at screening and at randomization Candidate for phototherapy and/or systemic therapy Men must agree to use a reliable method of birth control or remain abstinent during the study Women must agree to use reliable birth control or remain abstinent during the study and for at least 12 weeks after stopping treatment Exclusion Criteria: Pustular, erythrodermic, and/or guttate forms of psoriasis History of drug-induced psoriasis Prior use of etanercept Clinically significant flare of psoriasis during the 12 weeks prior to randomization Concurrent or recent use of any biologic agent Received non-biologic systemic psoriasis therapy or phototherapy (including psoralens and ultraviolet A [PUVA], ultraviolet B [UVB]) within the previous 4 weeks; or had topical psoriasis treatment within the previous 2 weeks prior to randomization Cannot avoid excessive sun exposure or use of tanning booths for at least 4 weeks prior to randomization and during the study Have participated in any study with interleukin 17 (IL-17) antagonists, including ixekizumab Serious disorder or illness other than plaque psoriasis Serious infection within the last 3 months Breastfeeding or nursing (lactating) women

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo for ixekizumab administered by two SC injections at Week 0, then one SC injection per Dosing Regimen 1 until Week 12. Placebo for etanercept administered by one SC injection twice weekly starting at Week 0 up to Week 12. At Week 12, participants are assigned to Dosing Regimen 2. | Drug: Placebo<br>* Administered SC<br>|
| Active Comparator: 50 mg etanercept<br>Administered by SC injections twice weekly starting at Week 0 up to Week 12. At Week 12, arm is assigned to Dosing Regimen 2 | Drug: 50 mg etanercept<br>* Administered SC<br>|
| Experimental: 80 mg ixekizumab Dosing Regimen 2<br>Administered by two 80 mg SC injections at Week 0, then one 80 mg SC injection per Dosing Regimen 2 until Week 264. | Drug: 80 mg ixekizumab<br>* Administered SC<br>* Other names: LY2439821;|
| Experimental: 80 mg ixekizumab Dosing Regimen 1<br>Administered by two 80 milligram (mg) subcutaneous (SC) injections at Week 0, then one 80 mg SC injection per Dosing Regimen 1 until Week 12. At Week 12, arm is assigned to Dosing Regimen 2. | Drug: 80 mg ixekizumab<br>* Administered SC<br>* Other names: LY2439821;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving a Static Physician Global Assessment (sPGA) of (0, 1) (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: sPGA) | The sPGA is a physician's determination of the participant's psoriasis lesions overall at a given time point categorized by descriptions for induration, erythema, and scaling. For the analysis of responses, the participant's psoriasis is assessed as clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5). An sPGA (0,1) response was defined as a post-baseline sPGA score of 0 or 1. | Week 12 | 
| Number of Participants Achieving Psoriasis Area and Severity Index ≥75% (PASI 75) Improvement (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: PASI) | The PASI combines assessments of the extent of body-surface involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of desquamation (scaling), erythema, and plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 for no psoriasis to 72 for the most severe disease. Participants achieving PASI 75 was defined as having an improvement of at least 75% in the PASI scores compared to baseline. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving an sPGA (0) (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: sPGA) | The sPGA is a physician's determination of the participant's psoriasis lesions overall at a given time point categorized by descriptions for induration, erythema, and scaling. For the analysis of responses, the participant's psoriasis is assessed as clear (0), minimal (1), mild (2), moderate (3), severe (4), or very severe (5). An sPGA (0) response was defined as a post-baseline sPGA score of 0. | Week 12 | 
| Number of Participants Achieving ≥90% (PASI 90) Improvement (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: PASI) | The PASI combines assessments of the extent of body-surface involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of desquamation (scaling), erythema, and plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 for no psoriasis to 72 for the most severe disease. Participants achieving PASI 90 were defined as having an improvement of at least 90% in the PASI scores compared to baseline. | Week 12 | 
| Number of Participants Achieving 100% (PASI 100) Improvement (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: PASI) | The PASI combines assessments of the extent of body-surface involvement in 4 anatomical regions (head, trunk, arms, and legs) and the severity of desquamation (scaling), erythema, and plaque induration/infiltration (thickness) in each region, yielding an overall score of 0 for no psoriasis to 72 for the most severe disease. Participants achieving PASI 100 were defined as having an improvement of at least 100% in the PASI scores compared to baseline. | Week 12 | 
| Number of Participants Achieving an Itch Numeric Rating Scale (NRS) ≥4 Point Reduction [Quality of Life and Outcome Assessments. Measures: Patient Reported Outcomes (PRO)] | The Itch NRS is a participant-administered single-item 11-point horizontal scale anchored at 0 and 10, with 0 representing no itch and 10 representing worst itch imaginable. Participants indicate their overall severity of itching from Psoriasis by circling the number that best describes the worst level of itching in the past 24 hours. | Week 12 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score | The DLQI is a simple, participant-administered, 10 question, validated, quality-of-life questionnaire that covers 6 domains: symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Response categories include not at all, a lot, and very much, with corresponding scores of 1, 2, and 3, respectively, and unanswered (not relevant) responses scored as 0. Totals range from 0 to 30 (less to more impairment), and a 5 point change from baseline is considered clinically relevant. Least Square (LS) Means in total DLQI score were calculated using Mixed Model Repeated Measures (MMRM) with baseline score as covariate, treatment, pooled center, visit and treatment-by-visit interaction as fixed effects. | Baseline, Week 12 | 
| Change From Baseline in Nail Psoriasis Severity Index (NAPSI) Score | The NAPSI is a numeric, reproducible, objective tool used to evaluate the severity of fingernail bed psoriasis and fingernail matrix psoriasis by area of involvement in the fingernail unit. The fingernail is divided with imaginary horizontal and longitudinal lines into quadrants. Each fingernail is given a score for fingernail bed psoriasis: 0 (none) to 4 (psoriasis in 4 quadrants of the nail) and fingernail matrix psoriasis (0 to 4) depending on the presence (score of 1) or absence (score of 0) of any of the features of fingernail bed and fingernail matrix psoriasis in each quadrant. The NAPSI score of a fingernail is the sum of scores in fingernail bed and fingernail matrix from each quadrant (maximum of 8). Each fingernail is evaluated, and the sum of all the fingernails is the total NAPSI score (range, 0 to 80). LS Means in NAPSI score were calculated using MMRM with baseline score as covariate, treatment, pooled center, visit and treatment-by-visit interaction as fixed effects. | Baseline, Week 12 | 
| Percent of Body Surface Area (BSA) Involvement of Psoriasis | Percentage involvement of psoriasis on each participants body surface area was assessed by the investigator on a continuous scale from 0% (no involvement) to 100% (full involvement), in which 1% corresponds to the size of the participant's hand (including palm, fingers and thumb). LS Means in BSA were calculated using MMRM with baseline BSA as covariate, treatment, pooled center, visit and treatment-by-visit interaction as fixed effects. | Week 12 | 
| Change From Baseline in Psoriasis Scalp Severity Index (PSSI) Score | PSSI is a composite score ranging from 0 (best) to 72 (worst), derived from the sum scores for erythema, induration, and desquamation multiplied by a score for the extent of scalp area involved. LS Means in PSSI score were calculated using MMRM with baseline score as covariate, treatment, pooled center, visit and treatment-by-visit interaction as fixed effects. | Baseline, Week 12 | 
| Change From Baseline in Quick Inventory of Depressive Symptomatology-Self Report 16 Items (QIDS-SR16) Total Score [Quality of Life and Outcome Assessments. Measures: Patient Reported Outcomes (PRO)] | The QIDS-SR16 is a self-administered, 16-item instrument in which a participant is asked to consider each statement as it relates to the way they have felt for the past 7 days. There is a 4-point scale for each item ranging from 0 (best) to 3 (worst). The 16 items are scored to give 9 individual depression domains (sad mood, concentration, self-criticism, suicidal ideation, interest, energy/fatigue, sleep disturbance [initial, middle and late insomnia or hypersomnia], decrease/increase in appetite/weight, and psychomotor agitation/retardation), which are summed to give a single score ranging from 0 to 27, with higher scores denoting greater symptom severity. LS Means in total QIDS-SR16 score were calculated using the analysis of covariance (ANCOVA) model with treatment, pooled center and baseline QIDS total score. | Baseline, Week 12 | 
| Change From Baseline in All Scores of the Work Productivity Activity Impairment Questionnaire-Psoriasis (WPAI-PSO) | The WPAI-PSO is a 6-item instrument used to assess the impact of psoriasis on productivity impairment within the past 7 days. It has four domains: absenteeism, presenteeism (reduced productivity while at work), an overall work impairment score, and impairment in daily activities performed outside of work. Four scores are derived as percentages: absenteeism, presenteeism, overall work impairment (absenteeism and presenteeism), and impairment in activities performed outside of work. Percentage is calculated as: each score * 100 and ranged from 0 to 100. Higher scores indicate greater impairment in productivity. LS Means in each WPAI-PSO score were calculated using the ANCOVA model with treatment, pooled center and baseline WPAI-PSO score. | Baseline, Week 12 | 
| Change From Baseline in Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey, Physical Component Summary (PCS) and Mental Component Summary (MCS) Scores | The SF-36 is a participant-reported outcome measure evaluating participant's health status. It comprises 36 items covering 8 domains: physical functioning, role physical, role emotional, bodily pain, vitality, social functioning, mental health, and general health. Items are answered on Likert scales of varying lengths. The 8 domains are regrouped into the PCS and MCS scores. The summary scores range from 0 to 100, with higher scores indicating better levels of function and/or better health. In this study, the SF-36 acute version was used, which has a 1 week recall period. LS Means in SF-36 score were calculated using the ANCOVA model with treatment, pooled center and baseline SF-36 score. | Baseline, Week 12 | 
| Change From Baseline in Patient's Global Assessment of Disease Severity | The Patient's Global Assessment of Disease Severity is a single-item participant-reported outcome measure on which participants are asked to rate the severity of their psoriasis today from 0 (Clear) = no psoriasis, to 5 (Severe) = the worst their psoriasis has ever been. LS Means in Patient's Global Assessment of Disease Severity score were calculated using MMRM with baseline score as covariate, treatment, pooled center, visit and treatment-by-visit interaction as fixed effects. | Baseline, Week 12 | 
| Number of Participants Achieving Palmoplantar PASI of ≥50% (PPASI 50) Improvement | Palmoplantar PASI is a composite score derived from the sum scores for erythema, induration, and desquamation multiplied by a score for the extent of palm and sole area involvement, ranging from 0 to 72. Participants achieving PPASI 50 were defined as having an improvement of at least 50% in the PPASI scores compared to baseline. | Week 12 | 
| Number of Participants Achieving Palmoplantar PASI of ≥75% (PPASI 75) Improvement | Palmoplantar PASI is a composite score derived from the sum scores for erythema, induration, and desquamation multiplied by a score for the extent of palm and sole area involvement, ranging from 0 to 72. Participants achieving PPASI 75 were defined as having an improvement of at least 75% in the PPASI scores compared to baseline. | Week 12 | 
| Number of Participants Achieving Palmoplantar PASI of 100% (PPASI 100) Improvement | Palmoplantar PASI is a composite score derived from the sum scores for erythema, induration, and desquamation multiplied by a score for the extent of palm and sole area involvement, ranging from 0 to 72. Participants achieving PPASI 100 were defined as having an improvement of 100% in the PPASI scores compared to baseline. | Week 12 | 
| Number of Participants With Treatment-Emergent Anti-Ixekizumab Antibodies | The percentage of participants with treatment-emergent positive anti-ixekizumab antibodies at any time post-baseline were summarized by treatment group. Percentage of participants with treatment-emergent positive anti-ixekizumab antibodies were calculated as: number of participants with an evaluable baseline sample and ≥1 evaluable post-baseline sample/number of participants in the analysis population * 100. | Week 12 |