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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company
ClinicalTrials.gov Identifier:
NCT01474512
First received: November 15, 2011
Last updated: April 20, 2016
Last verified: April 2016
Results First Received: April 20, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, 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
No text entered.

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  
Number of Participants  
[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)  
Gender  
[units: participants]
       
Female     128     143     142     413  
Male     303     289     291     883  
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  
Psoriasis Area and Severity Index (PASI) [2]
[units: units on a scale]
Mean (Standard Deviation)
  20.32  (8.641)     20.03  (7.304)     20.09  (7.992)     20.15  (7.992)  
Itch Numeric Rating Scale (NRS) [3]
[units: units on a scale]
Mean (Standard Deviation)
  7.0  (2.58)     7.0  (2.50)     7.2  (2.39)     7.1  (2.49)  
Dermatology-Specific Quality of Life Index (DLQI) Score [4]
[units: units on a scale]
Mean (Standard Deviation)
  12.8  (7.11)     13.2  (7.02)     13.4  (7.02)     13.1  (7.05)  
Nail Psoriasis Severity Index (NAPSI) (n=283, 281, 283) [5]
[units: units on a scale]
Mean (Standard Deviation)
  26.9  (20.492)     24.12  (18.243)     24.64  (18.916)     24.95  (19.238)  
Percent of Body Surface Area (BSA) involvement of Ps [6]
[units: percent of body surface]
Mean (Standard Deviation)
  27.4  (17.77)     27.4  (16.20)     28.2  (17.83)     27.7  (17.27)  
Psoriasis Scalp Severity Index (PSSI) (n=393, 413, 393) [7]
[units: units on a scale]
Mean (Standard Deviation)
  21.8  (15.70)     19.9  (14.83)     21.1  (14.69)     20.9  (15.08)  
Quick Inventory of Depressive Symptomatology-Self Reported 16 Items (QIDS-SR16) (n=430, 431, 431) [8]
[units: units on a scale]
Mean (Standard Deviation)
  4.7  (4.34)     5.0  (4.34)     4.5  (4.09)     4.8  (4.26)  
Work Productivity Activity Impairment Questionnaire-Psoriasis (WPAI-PSO) [9]
[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)  
Medical Outcomes Study 36-Item Short Form (SF36) Physical component (PCS) and Mental Component (MCS) [10]
[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)  
Patient's Global Assessment of Disease Severity (PatGA) (n=431, 430, 430) [11]
[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 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).
[2] 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).
[3] 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.
[4] 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.
[5] 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.
[6] 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).
[7] 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.
[8] 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.
[9] 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.
[10] 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.
[11] 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
  Show All Outcome Measures

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 ]

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 ]

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 ]

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 ]

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

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

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

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

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

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

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 ]

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

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 ]

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

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

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

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


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

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:
unchecked 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.
unchecked 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



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 )
Study First Received: November 15, 2011
Results First Received: April 20, 2016
Last Updated: April 20, 2016
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Canada: Health Canada
Denmark: Danish Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Germany: Paul-Ehrlich-Institut
Hungary: National Institute of Pharmacy
Italy: The Italian Medicines Agency
Japan: Pharmaceuticals and Medical Devices Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Romania: National Medicines Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration