Safety and Efficacy of Lebrikizumab (LY3650150) in Combination With Topical Corticosteroid in Moderate-to-Severe Atopic Dermatitis.

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled, parallel-group study which is 16 weeks in duration. The study is designed to evaluate the safety and efficacy of lebrikizumab when used in combination with topical corticosteroid (TCS) treatment compared with placebo in combination with TCS treatment for moderate-to-severe atopic dermatitis.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Trial To Evaluate The Efficacy and Safety of Lebrikizumab When Used In Combination With Topical Corticosteroid Treatment In Patients With Moderate-To-Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Biological: Lebrikizumab
* Other: Placebo
* Other: Topical Corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adult and adolescents (≥12 years to <18 years, and weighing ≥40 kg). Chronic AD (according to American Academy of Dermatology Consensus Criteria) that has been present for ≥1 year before the screening visit. Eczema Area and Severity Index (EASI) score ≥16 at the baseline visit. Investigator Global Assessment (IGA) score ≥3 (scale of 0 to 4) at the baseline visit ≥10% body surface area (BSA) of AD involvement at the baseline visit. History of inadequate response to treatment with topical medications. Exclusion Criteria: Participation in a prior lebrikizumab clinical study. Treatment with the following prior to the baseline visit: An investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer. Dupilumab within 8 weeks. B-cell-depleting biologics, including to rituximab, within 6 months. Other biologics within 5 half-lives (if known) or 16 weeks, whichever is longer. Treatment with a live (attenuated) vaccine within 12 weeks of the baseline visit or planned during the study. Uncontrolled chronic disease that might require bursts of oral corticosteroids. Evidence of active acute or chronic hepatitis History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening. History of malignancy, including mycosis fungoides, within 5 years before the screening visit, except completely treated in situ carcinoma of the cervix, completely treated and resolved non-metastatic squamous or basal cell carcinoma of the skin. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study.

Ages Eligible for Study
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Minimum Age: 12 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
Interventional Model Description: Randomized, double-blind, parallel group, placebo controlled
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lebrikizumab + Topical Corticosteroid<br>500 mg Lebrikizumab (2 x 250 mg) subcutaneous (SC) injections of lebrikizumab as a loading dose at Baseline and Week 2 followed by a single injection of 250 mg Lebrikizumab every 2 weeks (Q2W) from Week 4 until Week 14. Topical corticosteroid (TCS) will be initiated at Baseline in all participants and may be tapered or stopped, or restarted as needed, based on treatment response. | Biological: Lebrikizumab<br>* Subcutaneous injection<br>* Other names: DRM06;Other: Topical Corticosteroid<br>* Topical Corticosteroid<br>|
| Placebo Comparator: Placebo + Topical Corticosteroid<br>Two placebo subcutaneous (SC) injections as a loading dose at Baseline and Week 2 followed by a single injection of placebo every Q2W from Week 4 until Week 14. TCS will be initiated at Baseline in all participants and may be tapered or stopped, or restarted as needed, based on treatment response | Other: Placebo<br>* Subcutaneous injection<br>Other: Topical Corticosteroid<br>* Topical Corticosteroid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Investigator's Global Assessment (IGA) Score of 0 or 1 and a Reduction ≥2-points From Baseline to Week 16. | The IGA measures the investigator's global assessment of the participant's overall severity of their AD, based on a static, numeric 5-point scale from 0 (clear skin) to 4 (severe disease). The score is based on an overall assessment of the degree of erythema, papulation/induration, oozing/crusting, and lichenification. | Baseline to Week 16 | 
| Percentage of Participants Achieving Eczema Area and Severity Index (EASI-75) (≥75% Reduction From Baseline in EASI Score) at Week 16 | The EASI assesses objective physician estimates of 2 dimensions of atopic dermatitis - disease extent and clinical signs affected: 0 = 0%; 1 = 1-9%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100% and the severity of 4 clinical signs: (1) erythema, (2) edema/papulation, (3) excoriation, and (4) lichenification each on a scale of 0 to 3 (0 = none, absent; 1 = mild; 2 = moderate; 3 = severe) at 4 body sites (head/neck, trunk, upper limbs, and lower limbs). Half scores are allowed between severities 1, 2, and 3. The final EASI score was obtained by weight-averaging these 4 scores and will range from 0 to 72 (severe). The EASI responder is defined as a participant who achieves a ≥ 75% improvement from baseline in the EASI score. | Baseline to Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving EASI-90 (≥90% Reduction From Baseline in EASI Score) at Week 16 | The EASI assesses objective physician estimates of 2 dimensions of atopic dermatitis - disease extent and clinical signs affected: 0 = 0%; 1 = 1-9%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100% and the severity of 4 clinical signs: (1) erythema, (2) edema/papulation, (3) excoriation, and (4) lichenification each on a scale of 0 to 3 (0 = none, absent; 1 = mild; 2 = moderate; 3 = severe) at 4 body sites (head/neck, trunk, upper limbs, and lower limbs). Half scores are allowed between severities 1, 2, and 3. The final EASI score was obtained by weight-averaging these 4 scores and will range from 0 to 72 (severe). The EASI responder is defined as a participant who achieves a ≥ 90% improvement from baseline in the EASI score. | Baseline to Week 16 | 
| Percent Change in Pruritus Numerical Rating Scale (NRS) Score From Baseline to Week 16 | Pruritus NRS is an 11-point scale used by participants to rate their worst itch severity over the past 24 hours with 0 indicating No itch and 10 indicating Worst itch imaginable. Least Squares (LS) Mean was calculated using analysis covariance (ANCOVA) model includes treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA score as fixed factors. | Baseline, Week 16 | 
| Percentage of Participants With a Pruritus NRS of ≥4-Points at Baseline Who Achieve a ≥4-Point Reduction From Baseline to Week 16 | Pruritus NRS is an 11-point scale used by participants to rate their worst itch severity over the past 24 hours with 0 indicating No itch and 10 indicating Worst itch imaginable. | Baseline to Week 16 | 
| Percentage of Participants With a Pruritus NRS of ≥5-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 16 | Pruritus NRS is an 11-point scale used by participants to rate their worst itch severity over the past 24 hours with 0 indicating No itch and 10 indicating Worst itch imaginable. | Baseline to Week 16 | 
| Percent Change in EASI Score From Baseline at Week 16 | The EASI assesses objective physician estimates of 2 dimensions of atopic dermatitis - disease extent and clinical signs affected: 0 = 0%; 1 = 1-9%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100% and the severity of 4 clinical signs: (1) erythema, (2) edema/papulation, (3) excoriation, and (4) lichenification each on a scale of 0 to 3 (0 = none, absent; 1 = mild; 2 = moderate; 3 = severe) at 4 body sites (head/neck, trunk, upper limbs, and lower limbs). Half scores are allowed between severities 1, 2, and 3. The final EASI score was obtained by weight-averaging these 4 scores and will range from 0 to 72 (severe). LS Mean was calculated using ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA score (IGA 3 versus 4) as fixed factors. | Baseline, Week 16 | 
| Change From Baseline to Week 16 in Percent Body Surface Area (BSA) | The BSA affected by AD will be assessed for 4 separate body regions: head and neck, trunk (including genital region), upper extremities, and lower extremities (including the buttocks). Each body region will be assessed for disease extent ranging from 0% to 100% involvement. BSA was calculated using the participant's palm using the 1% rule, 1 palm was equivalent to 1% with estimates of the number of palms it takes to cover the affected AD area. Maximum number of palms were 10 palms for head and neck (10%), 20 palms for upper extremities (20%), 30 palms for trunk, including axilla and groin (30%), 40 palms for lower extremities, including buttocks (40%). Percent of BSA for a body region was calculated as = total number of palms in a body region * % surface area equivalent to 1 palm. Overall percent BSA of all 4 body regions ranges from 0% to 100 % with higher values representing greater severity of AD. | Baseline, Week 16 | 
| Percentage of Participants Achieving EASI-90 at Week 4 | The EASI assesses objective physician estimates of 2 dimensions of atopic dermatitis - disease extent and clinical signs affected: 0 = 0%; 1 = 1-9%; 2 = 10-29%; 3 = 30-49%; 4 = 50-69%; 5 = 70-89%; 6 = 90-100% and the severity of 4 clinical signs: (1) erythema, (2) edema/papulation, (3) excoriation, and (4) lichenification each on a scale of 0 to 3 (0 = none, absent; 1 = mild; 2 = moderate; 3 = severe) at 4 body sites (head/neck, trunk, upper limbs, and lower limbs). Half scores are allowed between severities 1, 2, and 3. The final EASI score was obtained by weight-averaging these 4 scores and will range from 0 to 72 (severe). The EASI responder is defined as a participant who achieves a ≥ 90% improvement from baseline in the EASI score. | Baseline to Week 4 | 
| Percent Change in Sleep-loss Score From Baseline to Week 16 | Sleep Loss due to interference of itch will be assessed by the participant. Participants rate their interference of itch on sleep based on a 5-point Likert scale [0 (not at all) to 4 (unable to sleep at all)]. Higher scores indicated a greater impact and worse outcome. Assessments will be recorded daily by the participant using an electronic diary. LS Mean was calculated using ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. . | Baseline, Week 16 | 
| Change From Baseline in Sleep-loss Score at Week 16 | Sleep Loss due to interference of itch will be assessed by the participant. Participants rate their interference of itch on sleep based on a 5-point Likert scale [0 (not at all) to 4 (unable to sleep at all)]. Higher scores indicated a greater impact and worse outcome. Assessments will be recorded daily by the participant using an electronic diary. LS Mean was calculated using ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. APD: All randomized participants, even if the participant does not take the assigned treatment, does not receive the correct treatment, or otherwise does not follow the protocol. | Baseline, Week 16 | 
| Percentage of Participants With a Pruritus NRS of ≥4-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 4 | The Pruritus NRS is an 11-point scale used by participants to assess their worst itch severity over the past 24 hours, with 0 indicating no itch and 10 indicating worst itch imaginable. | Baseline to Week 4 | 
| Percentage of Participants With a Pruritus NRS of ≥4-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 2 | The Pruritus NRS is an 11-point scale used by participants to assess their worst itch severity over the past 24 hours, with 0 indicating no itch and 10 indicating worst itch imaginable. | Baseline to Week 2 | 
| Percentage of Participants With a Pruritus NRS of ≥4-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 1 | The Pruritus NRS is an 11-point scale used by participants to assess their worst itch severity over the past 24 hours, with 0 indicating no itch and 10 indicating worst itch imaginable. | Baseline to Week 1 | 
| Percentage of Participants With a Pruritus NRS of ≥5-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 4 | The Pruritus NRS is an 11-point scale used by participants to assess their worst itch severity over the past 24 hours, with 0 indicating no itch and 10 indicating worst itch imaginable. | Baseline to Week 4 | 
| Percentage of Participants With a Pruritus NRS of ≥5-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 2 | The Pruritus NRS is an 11-point scale used by participants to assess their worst itch severity over the past 24 hours, with 0 indicating no itch and 10 indicating worst itch imaginable. | Baseline to Week 2 | 
| Percentage of Participants With a Pruritus NRS of ≥5-points at Baseline Who Achieve a ≥4-point Reduction From Baseline to Week 1 | The Pruritus NRS is an 11-point scale used by participants to assess their worst itch severity over the past 24 hours, with 0 indicating no itch and 10 indicating worst itch imaginable. | Baseline to Week 1 | 
| Percentage of Topical Corticosteroid (TCS)/Topical Calcineurin Inhibitors (TCI) Free Days From Baseline to Week 16 | Number of the total TCS/TCI free days divided by total number of days during the treatment period. The mixed model repeated measures (MMRM) includes treatment, visit, the interaction of treatment by-visit, geographic region, age group, baseline IGA score. | Baseline to Week 16 | 
| Median Time (Days) to TCS/TCI-free Use From Baseline to Week 16 | Days from first study drug injection to the day participant stopped using all TCS/TCI (if a participant started and stopped using low or midpotency TCS/TCI multiple times, use the last stop date as the stop date for this participant). | Baseline to Week 16 | 
| Percent Change in SCORing Atopic Dermatitis (SCORAD) From Baseline to Week 16 | The SCORAD index uses the rule of nines to assess disease extent and evaluates 6 clinical characteristics to determine disease severity: (1) erythema, (2) edema/papulation, (3) oozing/crusts, (4) excoriation, (5) lichenification, and (6) dryness on a scale of 0 to 3 (0=absence, 1=mild, 2=moderate, 3=severe). The SCORAD index also assesses subjective symptoms of pruritus and sleep loss with VAS where 0 is no itching or no trouble sleeping and 10 is unbearable itching or a lot of trouble sleeping. These 3 aspects: extent of disease (A: 0-1-2), disease severity (B: 0-18), & subjective symptoms (C: 0-20) combine using A/5 + 7*B/2+ C to give a maximum possible score of 103, where 0 = no disease and 103 = severe disease. LS Mean was calculated using the ANCOVA model with treatment group, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in Dermatology Life Quality Index (DLQI) at Week 16 | The DLQI is a 10-item, validated questionnaire used to assess the impact of skin disease on the quality of life of an affected person. The 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, and treatment, over the previous week. Response categories include Not at all, A little, A lot, and Very much, with corresponding scores of 0, 1, 2, and 3 respectively. Questions 3-10 also have an additional response category of Not relevant which is scored as 0. Questions are scored from 0 to 3, giving a possible total score range from 0 (no impact of skin disease on quality of life) to 30 (maximum impact on quality of life). A high score is indicative of a poor quality of life. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Percentage of Participants With a DLQI Score ≥4 Points at Baseline Who Achieve a ≥4 Points | The DLQI is a 10-item, validated questionnaire used to assess the impact of skin disease on the quality of life of an affected person. The 10 questions cover the following topics: symptoms, embarrassment, shopping and home care, clothes, social and leisure, sport, work or study, close relationships, sex, and treatment, over the previous week. Response categories include Not at all, A little, A lot, and Very much, with corresponding scores of 0, 1, 2, and 3 respectively. Questions 3-10 also have an additional response category of Not relevant which is scored as 0. Questions are scored from 0 to 3, giving a possible total score range from 0 (no impact of skin disease on quality of life) to 30 (maximum impact on quality of life). A high score is indicative of a poor quality of life. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline to Week 16 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) at Week 16 Health State Index | The EQ-5D-5L is a 2-part measurement. The first part is comprised of the following 5 participant-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses are used to derive the health state index scores using the United Kingdom (UK) algorithm, with scores ranging from -0.594 to 1, and the United States (US) algorithm, with scores ranging from -0.109 to 1, with higher score indicating better health state. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in European Quality of Life-5 Dimensions (EQ-5D) at Week 16 Visual Analog Score (VAS) | The EQ-5D-5L is a 2-part measurement. The second part is assessed using a VAS that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in Patient Oriented Eczema Measure (POEM) at Week 16 | POEM is a 7-item, validated, questionnaire used by the participant to assess disease symptoms over the last week. The participant is asked to respond to 7 questions on skin dryness, itching, flaking, cracking, sleep loss, bleeding and weeping. All 7 answers carry equal weight with a total possible score from 0 to 28 (answers scored as: No days=0; 1- 2 days = 1; 3-4 days = 2; 5-6 days = 3; everyday = 4). A high score is indicative of a poor quality of life. POEM responses will be captured using an electronic diary and transferred into the clinical database. LS Mean was calculated using MMRM model using treatment, baseline value, visit, the interaction of the baseline value-by-visit, the interaction of treatment by-visit as covariates, geographic region, age group, baseline IGA (3 versus 4) score as fixed. | Baseline, Week 16 | 
| Change From Baseline in Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety at Week 16 - Adults | PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. The PROMIS measures will be completed by the participant in the study clinic. PROMIS anxiety has 8 questions on Emotion Distress-Anxiety. Each question has 5 response options with values from 1 to 5. Total raw scores were converted to T-scores with higher scores indicating greater severity of symptoms. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in PROMIS Depression at Week 16 - Adults | PROMIS is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. The PROMIS measures will be completed by the participant in the study clinic. PROMIS depression has 8 questions on Emotion Distress-Depression. Each question has 5 response options with values from 1 to 5. Total raw scores were converted to T-scores with higher scores indicating greater severity of symptoms. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in PROMIS Anxiety at Week 16 - Pediatrics | PROMIS® is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. Participants ≤17 years will complete pediatric versions for the duration of the study. PROMIS anxiety has 8 questions on Emotion Distress-Anxiety (or Pediatric Anxiety Symptom). Each question has 5 response options with values from 1 to 5. Total raw scores were converted to T-scores with higher scores indicating greater severity of symptoms. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in PROMIS Depression at Week 16 - Pediatrics | PROMIS® is a set of person-centered measures that evaluates and monitors physical, mental, and social health in adults and children. Participants ≤17 years will complete pediatric versions for the duration of the study. PROMIS depression has 8 questions on Emotion Distress-Depression (or Pediatric Depressive Symptom). Each question has 5 response options with values from 1 to 5. Total raw scores were converted to T-scores with higher scores indicating greater severity of symptoms. LS Mean was calculated using the ANCOVA model with treatment, baseline value, and stratification factors of geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in Asthma Control Questionnaire (ACQ-5) Score at Week 16 in Participants Who Have Self-reported Comorbid Asthma | The ACQ-5 has been shown to reliably measure asthma control and distinguish participants with well-controlled asthma (score ≤0.75 points) from those with uncontrolled asthma (score ≥1.5 points). It consists of 5 questions that are scored on a 7- point Likert scale with a recall period of 1 week. The total ACQ-5 score is the mean score of all questions; a lower score represents better asthma control. LS Mean was calculated using ANCOVA with treatment, baseline value, geographic region, age group, baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 
| Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) at Week 16 | The CDLQI questionnaire is designed for use in children (4 to 16 years of age). It consists of 10 items that are grouped into 6 domains: symptoms & feelings, leisure, school or holidays, personal relationships, sleep, & treatment. The scoring of each question is: Very much =3; Quite a lot = 2; Only a little = 1; Not at all = 0. CDLQI total score is calculated by summing all 10 items responses, and has a range of 0 to 30 (higher scores are indicative of greater impairment). LS Mean was calculated using MMRM model which includes treatment, baseline value, visit, the interaction of the baseline value-by-visit as covariates, the interaction of treatment by-visit, geographic region, age group, and baseline IGA (3 versus 4) score as fixed factors. | Baseline, Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Eczema, Dermatitis, Dermatitis, Atopic, Skin Diseases