A Phase 3 Study in Participants With Moderate to Severe Psoriasis (UNCOVER-1)

Study Type:	Interventional
Study Design:	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Psoriasis
Interventions:	Drug: 80 mg Ixekizumab Dosing Regimens 1, 2, and 3; Drug: Placebo

  Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants who received Ixekizumab (ixe) and classified as responder (Resp, sPGA 0/1) in Induction (IND) were re-randomized to receive 80 mg ixe Q4W, Q12W or placebo (PBO) in Maintenance (MAIN) [Primary Population (Pop)]. Non-responders (Non-Resp, sPGA >1) in IND received 80 mg ixe Q4W, PBO Resp received PBO in MAIN (Secondary Pop).

Reporting Groups

	Description
Placebo- Induction Period	Placebo was administered as 2 subcutaneous (SC) injections every 2 weeks (Q2W) up to Week 10.
Ixe Q4W - Induction Period	160 milligrams (mg) ixe was administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection every 4 weeks (Q4W). Placebo was administered as 1 SC injection at Weeks 2, 6, and 10.
Ixe Q2W - Induction Period	160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W at Weeks 4, 6, 8, and 10.
Ixe/Placebo- Maintenance Period Primary Pop	Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56.
Ixe/Ixe Q12W - Maintenance Period Primary Pop	Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection every 12 weeks (Q12W) up to and including Week 56.
Ixe/Ixe Q4W - Maintenance Period Primary Pop	Participants who received 80 mg ixe Q2W or Q4W in Induction Period (Weeks 0 to 10) and classified as responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56.
Placebo Resp/Placebo - Maintenance Period Secondary Pop	Participants who received Placebo during the Induction Period (Weeks 0 to 10) and classified as responders and were administered placebo as 2 SC injections at Week 12 followed by placebo as 1 SC injection Q4W up to and including Week 56.
Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop	Participants who received placebo in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56.
Ixe Q4W Non-Resp/Ixe Q4W- Maintenance Period Secondary Pop	Participants who received 80 mg ixe Q4W in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56.
Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop	Participants who received 80 mg ixe Q2W in Induction Period (Weeks 0 to 10) and classified as non-responders were administered 80 mg ixe as 1 SC injection at Week 12 followed by 80 mg ixe as 1 SC injection Q4W up to and including Week 56.

Participant Flow for 2 periods

Period 1:   Induction Period

	Placebo- Induction Period	Ixe Q4W - Induction Period	Ixe Q2W - Induction Period	Ixe/Placebo- Maintenance Period Primary Pop	Ixe/Ixe Q12W - Maintenance Period Primary Pop	Ixe/Ixe Q4W - Maintenance Period Primary Pop	Placebo Resp/Placebo - Maintenance Period Secondary Pop	Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop	Ixe Q4W Non-Resp/Ixe Q4W- Maintenance Period Secondary Pop	Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop
STARTED	431	432	433	0	0	0	0	0	0	0
Received Study Drug	431	432	433	0	0	0	0	0	0	0
COMPLETED	407	408	415	0	0	0	0	0	0	0
NOT COMPLETED	24	24	18	0	0	0	0	0	0	0
Adverse Event	6	10	10	0	0	0	0	0	0	0
Lack of Efficacy	7	1	0	0	0	0	0	0	0	0
Withdrawal by Subject	6	6	5	0	0	0	0	0	0	0
Protocol Violation	3	6	0	0	0	0	0	0	0	0
Sponsor Decision	1	1	1	0	0	0	0	0	0	0
Lost to Follow-up	1	0	2	0	0	0	0	0	0	0

Period 2:   Maintenance Period

	Placebo- Induction Period	Ixe Q4W - Induction Period	Ixe Q2W - Induction Period	Ixe/Placebo- Maintenance Period Primary Pop	Ixe/Ixe Q12W - Maintenance Period Primary Pop	Ixe/Ixe Q4W - Maintenance Period Primary Pop	Placebo Resp/Placebo - Maintenance Period Secondary Pop	Placebo Non-Resp/Ixe Q4W - Maintenance Period Secondary Pop	Ixe Q4W Non-Resp/Ixe Q4W- Maintenance Period Secondary Pop	Q2W Non-Resp/Q4W - Maintenance Period Secondary Pop
STARTED	0	0	0	226	227 [1]	229	16	391	78	62
Received Study Drug	0	0	0	226	227	229	16	391	78	62
COMPLETED	0	0	0	24	108	177	6	350	62	44
NOT COMPLETED	0	0	0	202	119	52	10	41	16	18
Relapsed (sPGA ≥3)	0	0	0	186	111	39	9	0	0	0
Adverse Event	0	0	0	4	2	7	0	19	1	3
Withdrawal by Subject	0	0	0	6	2	3	1	6	3	1
Lost to Follow-up	0	0	0	3	3	0	0	2	1	1
Death	0	0	0	0	0	2	0	0	0	0
Investigator Decision	0	0	0	0	0	1	0	2	0	0
Clinical Relapse	0	0	0	1	0	0	0	0	0	0
Lack of Efficacy	0	0	0	1	0	0	0	11	11	12
Protocol Violation	0	0	0	1	0	0	0	1	0	1
Treated but Discontinued in Induction	0	0	0	0	1	0	0	0	0	0

[1]	One participant withdrew end of Induction but re-randomized and treated with maintenance dose ixe.

  Baseline Characteristics

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Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All randomized participants who received at least 1 dose of study drug.

Reporting Groups

	Description
Placebo	Placebo administered as 2 SC injections Q2W up to Week 10.
Ixe Q4W	160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q4W.
Ixe Q2W	160 mg ixe administered as 2 SC injections at Week 0 followed by 80 mg ixe as 1 SC injection Q2W up to Week 10.
Total	Total of all reporting groups

Baseline Measures

	Placebo	Ixe Q4W	Ixe Q2W	Total
Overall Participants Analyzed; [Units: Participants]	431	432	433	1296
Age; [Units: Years]; Mean (Standard Deviation)	46.4 (13.40)	45.6 (12.95)	45.1 (12.40)	45.7 (12.93)
Sex: Female, Male; [Units: Participants]; Count of Participants
Female	128 29.7%	143 33.1%	142 32.8%	413 31.9%
Male	303 70.3%	289 66.9%	291 67.2%	883 68.1%
Region of Enrollment; [Units: Participants]
Canada	77	69	66	212
Romania	8	3	2	13
Hungary	23	17	26	66
United States	146	156	159	461
Japan	13	12	8	33
Denmark	4	4	8	16
Poland	43	41	55	139
Italy	3	2	1	6
United Kingdom	7	7	7	21
Australia	19	15	8	42
Germany	88	106	93	287
Static Physician Global Assessment (sPGA) [1]; [Units: Participants]
sPGA=3	204	197	231	632
sPGA=4, 5	227	235	202	664
[1] 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. Participants Ps were assessed as 0 (clear), 1 (minimal), 2 (mild), 3 (moderate), 4 (severe), or 5 (very severe).
Psoriasis Area and Severity Index (PASI) [1]; [Units: Units on a scale]; Mean (Standard Deviation)	20.32 (8.641)	20.03 (7.304)	20.09 (7.992)	20.15 (7.992)
[1] PASI combines body surface involvement in 4 regions (head, trunk, arms, and legs), 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 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)]. Scores range from 0 (no Ps) to 72 (the most severe disease).
Itch Numeric Rating Scale (NRS) [1]; [Units: Units on a scale]; Mean (Standard Deviation)	7.0 (2.58)	7.0 (2.50)	7.2 (2.39)	7.1 (2.49)
[1] The Itch NRS is a participant-administered, 11-point horizontal scale anchored at 0 (no itch) and 10 (worst itch imaginable). Overall severity of a participant's itching from psoriasis (Ps) is indicated by circling the number that best describes the worst level of itching in the past 24 hours.
Dermatology-Specific Quality of Life Index (DLQI) Score [1]; [Units: Units on a scale]; Mean (Standard Deviation)	12.8 (7.11)	13.2 (7.02)	13.4 (7.02)	13.1 (7.05)
[1] 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 unanswered ("not relevant") responses were scored as "0." Total scores range from 0 to 30, with higher score indicating greater quality of life is impairment.
Nail Psoriasis Severity Index (NAPSI) (n=283, 281, 283) [1]; [Units: Units on a scale]; Mean (Standard Deviation)	26.9 (20.492)	24.12 (18.243)	24.64 (18.916)	24.95 (19.238)
[1] The NAPSI is a numeric, reproducible, objective tool to evaluate the severity of fingernail bed Ps and fingernail matrix Ps. 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 features of each fingernail bed and fingernail matrix Ps.The NAPSI score of a fingernail is the sum of scores in fingernail bed and fingernail matrix from each quadrant (maximum of 8). The sum of all fingernails equals the total NAPSI score with a range from 0 to 80. Higher scores indicated more severe psoriasis.
Percent of Body Surface Area (BSA) involvement of Ps [1]; [Units: Percent of body surface]; Mean (Standard Deviation)	27.4 (17.77)	27.4 (16.20)	28.2 (17.83)	27.7 (17.27)
[1] BSA is a physician rating of the percentage of involvement of Ps for each participant. BSA is assessed on a continuous scale from 0% (no involvement) to 100% (full involvement), where 1% corresponds to the size of the participants hand (includes the palm, fingers and thumb).
Psoriasis Scalp Severity Index (PSSI) (n=393, 413, 393) [1]; [Units: Units on a scale]; Mean (Standard Deviation)	21.8 (15.70)	19.9 (14.83)	21.1 (14.69)	20.9 (15.08)
[1] 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 to 72, with lower scores indicating less severity.
Quick Inventory of Depressive Symptomatology-Self Reported 16 Items (QIDS-SR16) (n=430, 431, 431) [1]; [Units: Units on a scale]; Mean (Standard Deviation)	4.7 (4.34)	5.0 (4.34)	4.5 (4.09)	4.8 (4.26)
[1] QIDS-SR16 is a participant-administered, 16-item instrument to assess the existence and severity of depression symptoms. A participant is asked to consider each statement as it relates to the way they have felt for the past 7 days and rate each on a 4-point scale: 0 (best) to 3 (worst). The sum of the 16 items corresponding to 9 depression domains (sad mood, concentration, self-criticism, suicidal ideation, interest, energy, sleep disturbance, change in appetite/weight, and psychomotor agitation/retardation) to give a total scores range from 0 to 27, higher scores indicate greater severity.
Work Productivity Activity Impairment Questionnaire-Psoriasis (WPAI-PSO) [1]; [Units: Units on a scale]; Mean (Standard Deviation)
Absenteeism (n=281, 287, 290)	4.5 (17.07)	4.0 (16.26)	5.7 (19.41)	4.7 (17.63)
Activity Impairment (n=431, 429, 432)	31.3 (29.29)	34.7 (28.83)	34.2 (28.99)	33.4 (29.05)
Presenteeism (297, 301, 299)	22.2 (25.85)	25.2 (27.22)	22.6 (26.46)	23.3 (26.53)
Work Productively Loss (n=279, 284, 288)	24.6 (27.90)	27.0 (27.90)	24.9 (28.77)	25.5 (28.18)
[1] WPAI-PSO is a self-administered, 6-item instrument used to assess the impact of Ps on productivity impairment within the past 7 days. WPAI-PSO has 4 domains: absenteeism, presenteeism (reduced productivity at work), an overall work impairment score and impairment in daily activities performed outside work. Four scores are derived as percentages: absenteeism, presenteeism (reduced productivity while at work), overall work impairment (absenteeism and presenteeism), and impairment in activities performed outside of work. Percentage = each score * 100. Greater scores indicate greater impairment.
Medical Outcomes Study 36-Item Short Form (SF36) Physical component (PCS) and Mental Component (MCS) [1]; [Units: Units on a scale]; Mean (Standard Deviation)
PCS (n=428, 428, 432)	46.92 (9.769)	47.34 (9.169)	46.58 (9.146)	46.95 (9.363)
MCS (n=428, 428, 432)	48.77 (11.182)	47.46 (11.655)	47.94 (11.535)	48.05 (11.463)
[1] The SF-36 is a self-reported instrument that measures the participant's health status during the previous 7 days. 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 in the PCS and MCS scores. Scores range from 0 to 100, with higher scores indicating better levels of function and/or better health.
Patient's Global Assessment of Disease Severity (PatGA) (n=431, 430, 430) [1]; [Units: Units on a scale]; Mean (Standard Deviation)	4.1 (0.95)	4.1 (0.88)	4.1 (0.94)	4.1 (0.92)
[1] The PatGA is a single-item self-reported instrument asking the participant to rate severity of their psoriasis "today" by circling a number on a 0 to 5 numeric rating scale from 0 (Clear = no psoriasis) to 5 (Severe = the worst their psoriasis has ever been).

  Outcome Measures

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1. Primary:

Percentage of Participants With Static Physician Global Assessment (sPGA) of 0 or 1 (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Ps Measure: sPGA) [ Time Frame: Week 12 ]

  Show Outcome Measure 1

2. Primary:

Percentage of Participants Achieving ≥75% Improvement in Ps Area and Severity Index (PASI75) (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Psoriasis Measure: PASI) [ Time Frame: Week 12 ]

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3. Secondary:

Percentage of Participants Achieving an sPGA of 0 (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Ps Measure: sPGA) [ Time Frame: Week 12 ]

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4. Secondary:

Percentage of Participants Achieving PASI 90% (PASI90) or 100% (PASI100) (Efficacy of Ixekizumab in Participants With Moderate to Severe Plaque Ps Measure: PASI) [ Time Frame: Week 12 ]

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5. Secondary:

Percentage of Participants Maintaining sPGA 0 or 1 After Re-Randomization at Start of Maintenance Dosing Period [ Time Frame: Week 60 ]

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6. Secondary:

Percentage of Participants With Itch Numeric Rating Scale (Itch NRS) Score ≥4 Point Reduction From Baseline [ Time Frame: Baseline, Week 12 ]

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7. Secondary:

Change From Baseline in Dermatology-Specific Quality of Life Index (DLQI) Score [ Time Frame: Baseline, Week 12 ]

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8. Secondary:

Change From Baseline in Nail Psoriasis Severity Index (NAPSI) [ Time Frame: Baseline, Week 12 ]

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9. Secondary:

Percent of Body Surface Area (BSA) Involvement of Ps [ Time Frame: Week 12 ]

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10. Secondary:

Change From Baseline in Psoriasis Scalp Severity Index (PSSI) [ Time Frame: Baseline, Week 12 ]

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11. Secondary:

Change From Baseline in All Scores of the Work Productivity Activity Impairment Questionnaire-Psoriasis (WPAI-PSO) (Quality of Life and Outcome Assessments. Measures: Participant Reported Outcomes [PRO]) [ Time Frame: Baseline, Week 12 ]

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12. Secondary:

Change From Baseline in Quick Inventory of Depressive Symptomatology-Self Reported 16 Items (QIDS-SR16) [ Time Frame: Baseline, Week 12 ]

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13. Secondary:

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) [ Time Frame: Baseline, Week 12 ]

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14. Secondary:

Change From Baseline in Patient's Global Assessment of Disease Severity (PatGA) [ Time Frame: Baseline, Week 12 ]

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15. Secondary:

Percentage of Participants Achieving Palmoplantar PASI (PPASI) of ≥50% (PPASI50), ≥75% (PPASI75), or 100% (PPASI100) Improvement [ Time Frame: Week 12 ]

  Show Outcome Measure 15

16. Secondary:

Pharmacokinetics (PK): Trough Concentration at Steady State (Ctrough ss) [ Time Frame: Weeks 12 and 24 ]

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17. Secondary:

Percentage of Participants With Anti-ixekizumab Antibodies [ Time Frame: Baseline through Week 12 ]

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  Serious Adverse Events

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  Other Adverse Events

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  Limitations and Caveats

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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information

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Certain Agreements:  

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is: The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo. The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo. Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Results Point of Contact:  

Name/Title: Chief Medical Officer
Organization: Eli Lilly and Company
phone: 800-545-5979

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Gordon KB, Blauvelt A, Papp KA, Langley RG, Luger T, Ohtsuki M, Reich K, Amato D, Ball SG, Braun DK, Cameron GS, Erickson J, Konrad RJ, Muram TM, Nickoloff BJ, Osuntokun OO, Secrest RJ, Zhao F, Mallbris L, Leonardi CL; UNCOVER-1 Study Group; UNCOVER-2 Study Group; UNCOVER-3 Study Group. Phase 3 Trials of Ixekizumab in Moderate-to-Severe Plaque Psoriasis. N Engl J Med. 2016 Jul 28;375(4):345-56. doi: 10.1056/NEJMoa1512711. Epub 2016 Jun 8.

Armstrong AW, Lynde CW, McBride SR, Ståhle M, Edson-Heredia E, Zhu B, Amato D, Nikaï E, Yang FE, Gordon KB. Effect of Ixekizumab Treatment on Work Productivity for Patients With Moderate-to-Severe Plaque Psoriasis: Analysis of Results From 3 Randomized Phase 3 Clinical Trials. JAMA Dermatol. 2016 Jun 1;152(6):661-9. doi: 10.1001/jamadermatol.2016.0269.

Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT01474512 History of Changes
Other Study ID Numbers:	12972; I1F-MC-RHAZ ( Other Identifier: Eli Lilly and Company )
First Submitted:	November 15, 2011
First Posted:	November 18, 2011
Results First Submitted:	April 20, 2016
Results First Posted:	May 27, 2016
Last Update Posted:	December 29, 2017