4083-006

Kyowa Kirin Co., Ltd

1-9-2, Otemachi, Chiyoda-ku, Tokyo, Japan, 100-0004

Regulatory Affairs Department, Kyowa Kirin Co., Ltd, +81 35205-7219,

Regulatory Affairs Department, Kyowa Kirin Co., Ltd, +81 35205-7219,

No

No

No

Final

12 Nov 2020

No

Yes

12 Nov 2020

No

To assess the efficacy of four dose regimens of KHK4083 compared to placebo as measured by the change from baseline in Eczema Area and Severity Index (EASI) score following multiple subcutaneous (SC) injections for 16 weeks in subjects with moderate to severe AD.

The Investigators were responsible for conducting the study in full accordance with the October 2013 revision of the Declaration of Helsinki, the GCP Guideline, approved by the ICH, and any applicable national and local laws and regulations. The Investigators complied with the protocol on which the Principal Investigator and the Sponsor had agreed and which had been approved in writing by the IRB/IEC. Before enrollment, the Investigator fully informed each subject who was considered appropriate for the study about the description of the study based on the Information for Subjects/ICF, which was provided separately and written in a language understandable for the subject. The subject was given sufficient time to decide whether or not to participate in the study, and the Investigator obtained written consent from the subject on a voluntary basis before the screening examinations. After the subject signed and dated the ICF, the Investigator who had conducted the informed consent discussion also signed and dated it. The Investigator provided the subject with a copy of the signed ICF and the Information for Subjects. The Investigator retained the original for the investigative site’s record in accordance with the policy of each site.

22 Sep 2018

No

No

Germany: 33

Canada: 25

Japan: 159

United States: 57

274

33

0

0

0

0

0

0

256

17

1

Overall trial (overall period)

Randomised - controlled

Yes

KHK4083

Solution for injection in vial

Subcutaneous use

150 mg of KHK4083 at Weeks 0 (Day 1), 4, 8, 12, 16, 20, 24, 28, and 32, done as three subcutaneous injections of 2 mL each.

Placebo

Solution for injection in vial

Subcutaneous use

150 mg of placebo at Weeks 2, 6, 10, 14, 18, 22, 26, 30, and 34, done as three subcutaneous injections of 2 mL each.

KHK4083

Solution for injection in vial

Subcutaneous use

600 mg of KHK4083 at Weeks 0 (Day 1), 4, 8, 12, 16, 20, 24, 28, and 32, done as three subcutaneous injections of 2 mL each.

Placebo

Solution for injection in vial

Subcutaneous use

600 mg of placebo at Weeks 2, 6, 10, 14, 18, 22, 26, 30, and 34, done as three subcutaneous injections of 2 mL each.

KHK4083

Solution for injection in vial

Subcutaneous use

300 mg of KHK4083 at Weeks 0 (Day 1), 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, and 34, done as three subcutaneous injections of 2 mL each.

KHK4083

Solution for injection in vial

Subcutaneous use

600 mg of KHK4083 at Weeks 0 (Day 1), 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, and 34, done as three subcutaneous injections of 2 mL each.

Placebo

Solution for injection in vial

Subcutaneous use

600 mg of placebo at Weeks 0 (Day 1), 2, 4, 6, 8, 10, 12, 14, and 16, done as three subcutaneous injections of 2 mL each.

KHK4083

Solution for injection in vial

Subcutaneous use

600 mg of KHK4083 at Weeks 18 (Day 127), 20, 22, 24, 26, 28, 30, 32, and 34, done as three subcutaneous injections of 2 mL each.

KHK4083 150 mg SC Q4W

KHK4083 600 mg SC Q4W

KHK4083 300 mg SC Q2W

KHK4083 600 mg SC Q2W

Placebo/KHK4083 600 mg

KHK4083 150 mg SC Q4W

KHK4083 600 mg SC Q4W

KHK4083 300 mg SC Q2W

KHK4083 600 mg SC Q2W

Placebo/KHK4083 600 mg

Full Analysis Set

One subject in the 600 mg Q4W group (US-09-08) was excluded from all analysis sets as the subject was not exposed to IP. Two subjects in the 150 mg Q4W group (JP-23-01 and US-08-05), 1 subject in the 600 mg Q4W group (JP-20-03),and 3 subjects in the 300 mg Q2W group (JP-13-05, JP-15-04, and US-02-08) were excluded from the full analysis set. Those 6 subjects had no evaluable EASI score after the start of IP administration until Week 16.

Per Protocol Set

One subject in the 600 mg Q4W group (US-09-08) was excluded from all analysis sets as the subject was not exposed to IP. Two subjects in the 150 mg Q4W group (JP-23-01 and US-08-05), 1 subject in the 600 mg Q4W group (JP-20-03), and 3 subjects in the 300 mg Q2W group (JP-13-05, JP-15-04, and US-02-08) were excluded from the per protocol set. Those 6 subjects had no evaluable EASI score after the start of IP administration until Week 16.

Safety Analysis Set

All subjects who received at least one dose of KHK4083. One subject in the 600 mg Q4W group (US-09-08) was excluded as the subject was not exposed to IP.

Pharmacokinetic Analysis Set

Subjects with at least one sample collected and analyzed for plasma drug concentration. 25 subjects in the placebo group were excluded from the PKS as they were not exposed to KHK4083 during the Treatment B period.

Primary

Every two weeks from Baseline to Week 16

The primary analysis will be performed in the percent change from baseline to Week 16 in EASI score, by applying ANCOVA with treatment, EASI score at baseline, and the following stratification factors: • Severity of AD (IGA=3, IGA=4) at baseline • Region (Japan, rest of world) • Previous use of biological products (Yes, No) for the treatment of AD at baseline

KHK4083 150 mg SC Q4W v Placebo/KHK4083 600 mg

109

Pre-specified

The primary analysis will be performed in the percent change from baseline to Week 16 in EASI score, by applying ANCOVA with treatment, EASI score at baseline, and the following stratification factors: • Severity of AD (IGA=3, IGA=4) at baseline • Region (Japan, rest of world) • Previous use of biological products (Yes, No) for the treatment of AD at baseline

Placebo/KHK4083 600 mg v KHK4083 600 mg SC Q4W

109

Pre-specified

The primary analysis will be performed in the percent change from baseline to Week 16 in EASI score, by applying ANCOVA with treatment, EASI score at baseline, and the following stratification factors: • Severity of AD (IGA=3, IGA=4) at baseline • Region (Japan, rest of world) • Previous use of biological products (Yes, No) for the treatment of AD at baseline

Placebo/KHK4083 600 mg v KHK4083 300 mg SC Q2W

109

Pre-specified

The primary analysis will be performed in the percent change from baseline to Week 16 in EASI score, by applying ANCOVA with treatment, EASI score at baseline, and the following stratification factors: • Severity of AD (IGA=3, IGA=4) at baseline • Region (Japan, rest of world) • Previous use of biological products (Yes, No) for the treatment of AD at baseline

Placebo/KHK4083 600 mg v KHK4083 600 mg SC Q2W

111

Pre-specified

In the EASI assessment, the severity of 4 elements of eczema (erythema, induration/papulation, excoriation, and lichenification) at each of 4 body regions (head and neck, trunk, upper extremities, and lower extremities) will be assessed on a scale of 0 to 3 (0 = None , 1 = Mild, 2 = Moderate, 3 = Severe). Half scores (1.5 and 2.5) are allowed, with the exception of 0.5. Any signs must be at least 1 (mild) in severity. In addition, the extent of eczema at each of the 4 body regions will be assessed on a scale of 0 to 6 (0 = 0%, 1 = 1% to 9%, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, 6 = 90% to 100%).

Secondary

Baseline to Week 16

In the EASI assessment, the severity of 4 elements of eczema (erythema, induration/papulation, excoriation, and lichenification) at each of 4 body regions (head and neck, trunk, upper extremities, and lower extremities) will be assessed on a scale of 0 to 3 (0 = None , 1 = Mild, 2 = Moderate, 3 = Severe). Half scores (1.5 and 2.5) are allowed, with the exception of 0.5. Any signs must be at least 1 (mild) in severity. In addition, the extent of eczema at each of the 4 body regions will be assessed on a scale of 0 to 6 (0 = 0%, 1 = 1% to 9%, 2 = 10% to 29%, 3 = 30% to 49%, 4 = 50% to 69%, 5 = 70% to 89%, 6 = 90% to 100%).

Secondary

Baseline to Week 16

Secondary

Baseline to Week 16

In the IGA, the Investigator will evaluate the overall skin symptoms of subjects at each visit on a 5-point scale ranging from 0 (clear) to 4 (severe).

Secondary

Every two weeks from Baseline to Week 16

The Investigator will calculate the percentage (%) of the total body surface area affected by AD.

Secondary

Baseline to Week 16

The worst degree of itch experienced during 24 hours before the time point will be assessed on a Numerical Rating Scale. The degree of itch will be scored on an 11-point scale, with 0 being "no itch" and 10 being the "worst itch imaginable."

Secondary

Baseline to Week 16

Daily sleep disturbance in the last 24 hours before the relevant time point will be assessed on a Numerical Rating Scale. Subjects will score the degree of their sleep disturbance on an 11-point scale ranging from 'no sleep loss' (0) to 'I cannot sleep at all" (10).

Secondary

Baseline to Week 16

DLQI (Dermatology Life Quality Index) consists of 6 subscales (symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment), which are scored from 0 to 3 on the basis of 10 questions. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more QoL is impaired.

Secondary

Baseline to Week 16

Adverse events were recorded for reporting from the subject’s written consent to participate in the study through the end of the study, up to 62 weeks (potential 6 week screening period up to Week 56).

The Investigator will inquire about AEs at all subject visits by asking the subject a non-leading question such as: “How have you been feeling since your last visit?” All AEs, whether observed by the Investigator or reported by the subject, must be collected. Each AE will be coded by the Sponsor according to MedRA.

23.1

KHK4083 150 mg SC Q4W

KHK4083 600 mg SC Q4W

KHK4083 300 mg SC Q2W

KHK4083 600 mg SC Q2W

Placebo