A Study of Intravenous MK-8226 in Participants With Moderate-to-Severe Atopic Dermatitis (MK-8226-003)

Study Overview
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Brief Summary
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This is a 3-part study to assess the safety, tolerability, efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MK-8226 in participants with moderate to severe atopic dermatitis. Part 1 (multiple rising dose study) objectives were to find the maximum tolerated dose (MTD) of MK-8226 and to assess safety and PK. Part 2 objectives were to determine safety, PK, and preliminary efficacy. Part 3 objectives were to further define safety and PK, and explore MK-8226 PK/PD to model the optimal dose range for future studies. The study was terminated early due to business reasons on 08 May 2014; final results from an analysis for Part 1 (efficacy, PK, safety, immunogenicity) and Part 2 (safety, immunogenicity) are summarized.

Detailed Description
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Part 1 of the study is a multiple rising dose assessment of the safety, tolerability, and pharmacokinetics of MK-8226 for a period of 12 weeks followed by a 20-week off-treatment follow-up period. Part 2 of the study is an assessment of the safety, tolerability, and efficacy of MK-8226 for 12 weeks followed by a 20-week off-treatment follow-up period. In Part 3 of the study, participants will be treated with MK-8226 for a period of 12 weeks followed by a 20-week off-treatment follow-up period to evaluate pharmacokinetic and pharmacokinetic correlations to assist with modeling the dose range planned for further studies.

Official Title
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A Phase Ib Randomized, Double-Blinded, Placebo-Controlled Multiple Rising Dose Clinical Trial to Evaluate the Safety, Efficacy, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Intravenous MK-8226 in Patients With Moderate to Severe Atopic Dermatitis

Conditions
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Atopic Dermatitis

Intervention / Treatment
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* Drug: MK-8226
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body weight >=40 kg Clinical diagnosis of atopic dermatitis for at least 6 months prior Candidate for systemic or phototherapy (i.e., failed topical treatment) Moderate-to-severe disease as defined by Body Surface Area (BSA) ≥10%, EASI ≥12, and IGA ≥3 No clinically significant abnormality on electrocardiogram No history of active or latent tuberculosis (TB) and no signs or symptoms suggestive of TB No history of active or latent TB and no signs or symptoms suggestive of TB History of inadequate response to a stable (≥ 1 month) regimen of topical corticosteroids or calcineurin inhibitors within 3 months before the screening visit Exclusion Criteria: Concurrent significant skin disease Any significant organ dysfunction within 6 months prior History of clinically significant heart disease History of neoplastic disease Positive for hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) Infection requiring oral antibiotics within 2 weeks prior Receipt of a live virus vaccine within 4 weeks prior Inability to refrain from topical or systemic therapy during course of the study Had major surgery or donated or lost >=1 unit of blood within 4 weeks prior Participation in another study within 4 weeks prior Current or regular user of illicit drugs or a history of drug or alcohol abuse within 1 year prior Pregnant, breast-feeding, or anticipated to conceive during the course of the study

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: Part 1: MK-8226 0.3 mg/kg<br>MK-8226 administered intravenously (IV) at a weight-based dose every 2 weeks for a period of 12 weeks. | Drug: MK-8226<br>* MK-8226 administered IV at a weight-based dose every 2 weeks for 12 weeks.<br>|
| Experimental: Part 1: MK-8226 1 mg/kg<br>MK-8226 administered IV at a weight-based dose every 2 weeks for a period of 12 weeks. | Drug: MK-8226<br>* MK-8226 administered IV at a weight-based dose every 2 weeks for 12 weeks.<br>|
| Experimental: Part 1: MK-8226 3 mg/kg<br>MK-8226 administered IV at a weight-based dose every 2 weeks for a period of 12 weeks. | Drug: MK-8226<br>* MK-8226 administered IV at a weight-based dose every 2 weeks for 12 weeks.<br>|
| Experimental: Part 1: MK-8226 10 mg/kg<br>MK-8226 administered IV at a weight-based dose every 2 weeks for a period of 12 weeks. | Drug: MK-8226<br>* MK-8226 administered IV at a weight-based dose every 2 weeks for 12 weeks.<br>|
| Placebo Comparator: Part 1: Placebo (pooled)<br>Dose-matched placebo administered IV every 2 weeks for a period of 12 weeks. | Drug: Placebo<br>* Placebo administered IV every 2 weeks for a period of 12 weeks.<br>|
| Experimental: Part 2: MK-8226 3 mg/kg<br>MK-8226 administered IV at a weight-based dose every 2 weeks for a period of 12 weeks. | Drug: MK-8226<br>* MK-8226 administered IV at a weight-based dose every 2 weeks for 12 weeks.<br>|
| Placebo Comparator: Part 2: Placebo<br>Placebo administered IV every 2 weeks for a period of 12 weeks. | Drug: Placebo<br>* Placebo administered IV every 2 weeks for a period of 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced at Least One Adverse Event | An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. | Up to 32 Weeks | 
| Number of Participants Who Discontinued Study Drug Due to an Adverse Event | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. | Up to 12 Weeks | 
| Change From Baseline in the Eczema Area and Severity Index (EASI) for Study Part 1 | Reduction from baseline in EASI at Week 12 (interim analysis data). The EASI assesses intensity of four lesion characteristics (erythema, infiltration/population, excoriation, lichenification) each rated on a scale of 0 (absent) to 3 (severe) across four regions (head, trunk, upper and lower extremities). Affected areas in each region are assessed as percentage of body surface (head [10%], trunk [30%], upper extremities [20%], and lower extremities [40%]). The total score is a sum of each region score and can range from 0 (absent disease) to 72 (severe disease). | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Chemokine (C-C Motif) Ligand 17 (CCL17) Level in Study Part 2 | CCL17 is a pro-allergic chemokine that is assessed in human plasma. Levels of CCL17 are increased in allergic disease states. | Baseline, 48 Hours, Week 2, Week 4, Week 12, Week 16 | 
| Plasma Chemokine (C-C Motif) Ligand 22 (CCL22) Level in Study Part 2 | CCL22 is a pro-allergic chemokine that is assessed in human plasma. Levels of CCL22 are increased in allergic disease states. | Baseline, 48 Hours, Week 2, Week 4, Week 12, Week 16 | 
| Area Under the Concentration-time Curve of MK-8226 From Time 0 to Tau (AUC0-tau) Following Multiple Intravenous Dose Administration | AUC(0-tau) defined as AUC from time zero to tau where tau is the dosing interval (312 hours) was determined for the first and last periods of MK-8226 dosing. MK-8226 was administered on Days 1, 14, 28, 42, 56, and 70. Blood concentrations of MK-8226 were determined on Days 1 (incl. predose), 3, 5, 9, 14 (incl. predose), 70 (incl. predose), 72, 74, 84. The placebo group is not included; this endpoint evaluated only the MK-8226 groups. No analysis was performed for Part 2 non-safety secondary endpoints after the Part 1 primary endpoint (Change from BL in EASI) did not demonstrate adequate effect in an interim futility analysis. | Days 1, 3, 5, 9, 14, 70, 72, 74, 84 | 
| AUC From Time 0 to Last Measurement (AUC0-last) of MK-8226 Following Multiple Intravenous Dose Administration | AUC0-last defined as AUC up to the last measured concentration was determined for the last period of dosing (starting Week 10 [Day 70]) up to the last measurement. MK-8226 was administered on Days 1, 14, 28, 42, 56, and 70. Blood concentrations of MK-8226 were determined on Days 70 (incl. predose), 72, 74, 84, 98, 112, 140, 168, 196, and 224. The placebo group is not included; this endpoint evaluated only the MK-8226 groups. No analysis was performed for Part 2 non-safety secondary endpoints after the Part 1 primary endpoint (Change from BL in EASI) did not demonstrate adequate effect in an interim futility analysis. | Days 70, 72, 74, 84, 98, 112, 140, 168, 196, 224 | 
| Maximum Serum Concentration (Cmax) of MK-8226 Following Multiple Dose Intravenous Administration | Cmax was determined for the first and last periods of MK-8226 dosing. MK-8226 was administered on Days 1, 14, 28, 42, 56, and 70. Blood concentrations of MK-8226 were determined on Days 1 (incl. predose), 3, 5, 9, 14 (incl. predose), 70 (incl. predose), 72, 74, and 84. The placebo group is not included; this endpoint evaluated only the MK-8226 groups. No analysis was performed for Part 2 non-safety secondary endpoints after the Part 1 primary endpoint (Change from BL in EASI) did not demonstrate adequate effect in an interim futility analysis. | Days 1, 3, 5, 9, 14, 70, 72, 74, 84 | 
| Clearance (CL) of MK-8226 Following Multiple Dose Intravenous Administration | CL, the volume of plasma cleared of drug per unit time, was determined for the last period of dosing (starting Week 10 [Day 70]) in the treatment period. MK-8226 was administered on Days 1, 14, 28, 42, 56, and 70. Blood concentrations of MK-8226 were determined on Days 1 (incl. predose), 3, 5, 9, 14 (incl. predose), 28 (incl. predose), 42 (incl. predose), 56 (incl. predose), 70 (incl. predose), 72, 74, and 84. The placebo group is not included; this endpoint evaluated only the MK-8226 groups. No analysis was performed for Part 2 non-safety secondary endpoints after the Part 1 primary endpoint (Change from BL in EASI) did not demonstrate adequate effect in an interim futility analysis. | Days 1, 3, 5, 9, 14, 28, 42, 56, 70, 72, 74, 84 | 
| Volume of Distribution (Vd) of MK-8226 Following Multiple Intravenous Administration | Vd, a theoretical approximation of degree to which the drug distributes in body tissue rather than plasma (higher Vd indicates greater tissue distribution), was determined for the last period of dosing (starting Week 10 [Day 70]) in the treatment period. MK-8226 was administered on Days 1, 14, 28, 42, 56, and 70. Blood concentrations of MK-8226 were determined on Days 70 (incl. predose), 72, 74, 84, 98, 112, 140, 168, 196, and 224. The placebo group is not included; this endpoint evaluated only the MK-8226 groups. No analysis was performed for Part 2 non-safety secondary endpoints after the Part 1 primary endpoint (Change from BL in EASI) did not demonstrate adequate effect in an interim futility analysis. | Days 70, 72, 74, 84, 98, 112, 140, 168, 196, 224 | 
| Terminal Half Life (t1/2) of MK-8226 Following Multiple Dose Intravenous Administration | t1/2, the time needed for the concentration of drug to reach half the initial concentration, was determined for the last period of dosing (starting Week 10 [Day 70]) up to the last measurement. MK-8226 was administered on Days 1, 14, 28, 42, 56, and 70. Blood concentrations of MK-8226 were determined on Days 70 (incl. predose), 72, 74, 84, 98, 112, 140, 168, 196, and 224. The placebo group is not included; this endpoint evaluated only the MK-8226 groups. No analysis was performed for Part 2 non-safety secondary endpoints after the Part 1 primary endpoint (Change from BL in EASI) did not demonstrate adequate effect in an interim futility analysis. | Days 70, 72, 74, 84, 98, 112, 140, 168, 196, 224 | 
| Change From Baseline in the Eczema Area and Severity Index (EASI) for Study Part 2 | The EASI assesses intensity of four lesion characteristics (erythema, infiltration/population, excoriation, lichenification) each rated on a scale of 0 (absent) to 3 (severe) across four regions (head, trunk, upper and lower extremities). Affected areas in each region are assessed as percentage of body surface (head [10%], trunk [30%], upper extremities [20%], and lower extremities [40%]). The total score is a sum of each region score and can range from 0 (absent disease) to 72 (severe disease). | Baseline, Week 4, Week 8, Week 24 | 
| Percentage of Participants With an Investigator Global Assessment (IGA) Score of Clear or Almost Clear in Study Part 2 | Percentage of participants achieving an IGA of atopic dermatitis of clear-0 or almost clear-1. The IGA is a six-point scale measuring the severity of disease at time of physical examination of the participant by the physician. The IGA is scored 0 (Clear) to 5 (Very severe disease). | Baseline, Week 4, Week 8, Week 12, Week 24 | 
| Change From Baseline in the Scoring Atopic Dermatitis Scale (SCORAD) in Study Part 2 | The SCORAD index scale combines 1) intensity of six lesion characteristics (erythema, edema/papulation, oozing/crusts, excoriations, lichenification, dryness) as assessed by the physician on a scale of 0 (absent) to 3 (severe) across four regions (head, trunk, upper and lower extremities) along with 2) subjective symptoms of pruritus and sleep disturbance as reported by the patient on a visual analog scale (VAS) from 1 to 10 cm (increasing severity). Physician assessment of affected areas in each region is made as percentage of body surface (head [10%], trunk [30%], upper extremities [20%], and lower extremities [40%]). The final SCORAD index score, ranging from 0 (absent disease) to 103 (severe disease), is calculated according to the weighted formula: (0.2 x area) + (3.5 x [sum of intensity score for each of the 6 items]) + participant's subjective score. | Baseline, Week 4, Week 12, Week 24 | 
| Change From Baseline in Participant Pruritus in Study Part 2 | Skin pruritus (itching) is a typical characteristic of atopic dermatitis. Participant subjective assessment of pruritus (component of SCORAD) is rated on a VAS ranging from 1 to 10 cm (increasing severity). | Baseline, Week 4, Week 12, Week 24 | 
| Change From Baseline in Participant Sleep Disturbance in Study Part 2 | Sleep disturbance (sleep loss, disruption, or interference) due to unremitting pruritus and other causes is a quality of life issue in moderate to severe atopic dermatitis. Participant subjective assessment of sleep disturbance (component of SCORAD) over the past 3 days is rated on a VAS ranging from 1 to 10 cm (increasing severity). | Baseline, Week 4, Week 12, Week 24 | 
| Number of Participants Requiring As-Needed Oral Antihistamines as Rescue Medication in Study Part 2 | Oral antihistamines (i.e., diphenhydramine, acrivastine fenistil) were provided as as-needed rescue medication for severe pruritus. | Up to Week 12 | 
| Percentage of Participants With >=50% Improvement in EASI Score | The EASI assesses intensity of four lesion characteristics (erythema, infiltration/population, excoriation, lichenification) each rated on a scale of 0 (absent) to 3 (severe) across four regions (head, trunk, upper and lower extremities). Affected areas in each region are assessed as percentage of body surface (head [10%], trunk [30%], upper extremities [20%], and lower extremities [40%]). The total score is a sum of each region score and can range from 0 (absent disease) to 72 (severe disease). | Baseline, Week 12, Week 24 | 
| Number of Participants Positive for Anti-Drug Antibody (ADA) Formation | Testing for ADA positivity and neutralizing response and antibody titre quantification are performed with blood (serum) samples collected at baseline (Day 1 predose) and Days 14, 28, 42, 56, 74, 112, and 224. Neutralizing response refers to ADA neutralizing interference with study drug assessed in vitro. Non-Treatment emergent ADA refers to presence of ADAs (as determined by assay) in the absence of treatment with study drug (i.e., at predose). | Days 1 (predose) and Days 14, 28, 42, 56, 74, 112, and 224 |