A Phase 3 Study in Participants With Moderate to Severe Psoriasis (UNCOVER-2)

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 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

Conditions
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Psoriasis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Present with chronic plaque psoriasis based on a confirmed diagnosis of chronic plaque psoriasis for at least 6 months prior to first dose of study drug At least 10% Body Surface Area (BSA) of psoriasis at screening and at first dose of study drug 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 first dose of study drug 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 |
| --- | --- |
| Experimental: 80 mg ixekizumab Dosing Regimen 1<br>Administered by two 80 mg subcutaneous (SC) injections at Week 0, then one 80 mg SC injection per Dosing Regimen 1 until Week 12. At Week 12, ixekizumab responders are re-randomized to placebo, Dosing Regimen 2 or Dosing Regimen 3. Ixekizumab non-responders are assigned to Dosing Regimen 2. | Drug: 80 mg ixekizumab Dosing Regimen<br>* Administered SC<br>* Other names: LY2439821;|
| 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 12. At Week 12, ixekizumab responders are re-randomized to placebo, Dosing Regimen 2 or Dosing Regimen 3. Ixekizumab non-responders are assigned to Dosing Regimen 2. | Drug: 80 mg ixekizumab Dosing Regimen<br>* Administered SC<br>* Other names: LY2439821;|
| Experimental: 80 mg ixekizumab Dosing Regimen 3<br>Dosing Regimen 3 is not used until Week 12. At Week 12, ixekizumab responders re-randomized to this arm will receive Dosing Regimen 3. | Drug: 80 mg ixekizumab Dosing Regimen<br>* Administered SC<br>* Other names: LY2439821;|
| Active Comparator: 50 mg etanercept<br>Administered by one 50 mg SC injection twice weekly starting at Week 0 up to Week 12. At Week 12, etanercept responders are assigned to placebo, and nonresponders to Dosing Regimen 2. | Drug: 50 mg etanercept<br>* Administered SC<br>|
| Placebo Comparator: Placebo for ixekizumab<br>Placebo for ixekizumab administered by two SC injections at Week 0, then one SC injection per Dosing Regimen 1 until Week 12. At Week 12, placebo responders are assigned to placebo, and nonresponders to Dosing Regimen 2. Placebo for etanercept administered by one SC injection twice weekly starting at Week 0 up to Week 12 was used to blind etanercept injections for Dosing Regimen 1, Dosing Regimen 2, and Placebo Comparator groups. | Drug: Placebo<br>* Administered SC<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With a Static Physician Global Assessment (sPGA) of (0,1) (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: Static Physician Global Assessment [sPGA]) | The sPGA is the physician's determination of the participant's Psoriasis (Ps) lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participant's Ps was assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe). An sPGA responder was defined as having a post-baseline sPGA score of 0 or 1 with at least a 2-point improvement from baseline. | Week 12 | 
| Percentage of Participants Achieving Psoriasis Area and Severity Index (PASI) ≥75% (PASI75) Improvement (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: Psoriasis Area and Severity Index [PASI]) | The PASI combines the extent of body surface involvement in 4 anatomical regions (head, trunk, arms, and legs). For each region the percent area of skin involved was estimated from 0 (0%) to 6 (90%-100%) and severity was estimated by clinical signs of erythema, induration and scaling with a scores range from 0 (no involvement) to 4 (severe involvement). Each area is scored separately and the scores then combined for the final PASI. Final PASI calculated as: sum of severity parameters for each region * area score * weighing factor (head [0.1], upper limbs [0.2], trunk [0.3], lower limbs [0.4]). Overall scores range from 0 (no Ps) to 72 (the most severe disease). Participants achieving PASI75 were defined as having an improvement of ≥75% in the PASI score compared to baseline. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving an sPGA (0) (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: [sPGA]) | The sPGA is the physician's determination of the participant's Ps lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participant's Ps was assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe). | Week 12 | 
| Percentage of Participants Achieving PASI 90% (PASI90) (Efficacy of Ixekizumab in Participants With Moderate to Severe Chronic Plaque Psoriasis. Measure: [PASI]) | The PASI combines the extent of body surface involvement in 4 anatomical regions (head, trunk, arms, and legs). For each region the percent area of skin involved was estimated from 0 (0%) to 6 (90%-100%) and severity was estimated by clinical signs of erythema, induration and scaling with a scores range from 0 (no involvement) to 4 (severe involvement). Each area is scored by itself and the scores were then combined for the final PASI. Final PASI calculated as: sum of severity parameters for each region * area score * weighing factor (head [0.1], upper limbs [0.2], trunk [0.3], lower limbs [0.4]). Overall scores range from 0 (no Ps) to 72 (the most severe disease). Participants achieving PASI90 were defined as having an improvement of ≥90% in the PASI score compared to baseline. | Week 12 | 
| Percentage of Participants Achieving PASI 100% (PASI100) | The PASI combines the extent of body surface involvement in 4 anatomical regions (head, trunk, arms, and legs). For each region the percent area of skin involved was estimated from 0 (0%) to 6 (90%-100%) and severity was estimated by clinical signs of erythema, induration and scaling with a scores range from 0 (no involvement) to 4 (severe involvement). Each area is scored by itself and the scores were then combined for the final PASI. Final PASI calculated as: sum of severity parameters for each region * area score * weighing factor (head [0.1], upper limbs [0.2], trunk [0.3], lower limbs [0.4]). Overall scores range from 0 (no Ps) to 72 (the most severe disease). Participants achieving PASI100 were defined as having an improvement of 100% in the PASI score compared to baseline. | Week 12 | 
| Percentage of Participants Maintaining an sPGA (0,1) From Week 12 After Re-randomization at Start of Maintenance Dosing Period to Week 60 | The sPGA is the physician's determination of the participant's Ps lesions overall at a given time point. Lesions were categorized by descriptions for induration, erythema, and scaling. Participant's Ps was assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe). | Week 60 | 
| Percentage of Participants With Itching Severity (Itch Numeric Rating Scale [NRI]) Score ≥4 Point Reduction From Baseline | The Itch Numeric Rating Scale (NRS) is a participant-administered, 11-point horizontal scale anchored at 0 and 10, with 0 representing no itch and 10 representing worst itch imaginable. The number and percentage of participants achieving an Itch NRS ≥4 point reduction from baseline were presented by treatment group for participants who had a baseline Itch NRS ≥4. Describes worst level of itching in past 24 hours. | Week 12 | 
| Change From Baseline in Dermatology-Specific Quality of Life Index (DLQI) Total Score (Quality of Life and Outcome Assessments. Measures: Participant Reported Outcomes [PRO]) | DLQI is a participant-administered, 10-question, validated, quality-of-life questionnaire that covers 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. Response categories include 0 (not at all), 1 (a little), 2 (a lot), and 3 (very much); and not relevant and unanswered responses were scored as 0. Total scores range from 0 to 30, with higher score indicating greater quality of life impairment. A 5-point change from baseline is considered clinically relevant. Least Squares (LS) Mean change from baseline was 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) | The NAPSI scale is used to evaluate the severity of fingernail bed Ps and fingernail matrix Ps. The fingernail bed and fingernail matrix are each divided into quadrants. Each fingernail is given a score for fingernail bed Ps and fingernail matrix Ps, each with scores of 0 (none) to 4 (Ps in all 4 quadrants), depending on the presence (score of 1) or absence (score of 0) of Ps in each quadrant of the fingernail bed or matrix. The NAPSI score of a fingernail is the sum of scores from each quadrant of the fingernail bed and fingernail matrix (maximum of 8). The total NAPSI score equals the sum of all fingernails and ranges from 0 to 80 with higher scores indicating more severe Ps. LS mean change from baseline in NAPSI score was 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 Psoriasis Scalp Severity Index (PSSI) Score | The PSSI is a physician assessment of erythema, induration and desquamation and percent of scalp that is covered with a scores range from 0 (none) to 4 (very severe). The composite score is derived from the sum of scores for erythema, induration, and desquamation multiplied by the score recorded for the extent of the scalp area involved, 1 (<10%) to 6 (90%-100%) with a total scores range from 0 (less severity) to 72 (more severity), with lower scores indicating less severity. LS mean change from baseline in PSSI score was calculated using MMRM with baseline score as a covariate, treatment, pooled center, visit, and treatment-by-visit interaction as fixed effects. | Baseline, Week 12 | 
| Change From Baseline in Percent of Body Surface Area (BSA) Involvement of Psoriasis | The percentage involvement of psoriasis on each participant's 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 mean change from baseline in BSA was calculated using MMRM with baseline BSA as a 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 | 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 mean change from baseline in total QIDS-SR16 score was 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 and has four domains, namely, 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 ranges from 0 to 100; greater scores indicate greater impairment. LS mean change from baseline in each WPAI-PSO score was calculated using the (ANCOVA) model with treatment, pooled center and baseline WPAI value. | Baseline, Week 12 | 
| Change From Baseline in Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) and 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 mean change from baseline in SF-36 score was 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 (PatGA) of Disease Severity | The Patient's Global Assessment of Disease Severity is a single-item patient reported outcome measure on which participants are asked to rate by circling a number on a 0 to 5 NRS the severity of their psoriasis today from 0 (Clear) = no psoriasis to 5 (Severe) = the worst their psoriasis has ever been. LS mean change from baseline in patient's global assessment of disease severity score was calculated using (MMRM) with baseline score as a covariate, treatment, pooled center, visit, and treatment-by-visit interaction as fixed effects. | Baseline, 12 weeks | 
| Percentage of Participants Achieving Palmoplantar PASI (PPASI) of ≥50% (PPASI50), ≥75% (PPASI75) or 100% (PPASI100) Improvement | The 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. The PPASI was only assessed if participants have palmoplantar psoriasis at baseline. Participants achieving PPASI50, PPASI75 or PASI100 were defined as having an improvement of at least 50%, 75%, or of 100%, respectively, in the PPASI scores compared to baseline. | Week 12 | 
| Percentage of Participants With Anti-Ixekizumab Antibodies | Percentage of participants with treatment-emergent positive anti-ixekizumab antibodies was summarized by treatment group. Percentage was calculated based on the # of evaluable participants and was calculated by number of participants with treatment-emergent positive anti-ixekizumab antibodies / number of evaluable participants * 100%. | Baseline to Week 12 |