Pediatric Study in Children and Adolescents With Severe Plaque Psoriasis

A Randomized, Double-blind, Placebo- and Active Controlled Multicenter Trial to Demonstrate Efficacy of Subcutaneous Secukinumab Compared to Placebo and Etanercept (in a Single-blinded Arm) After Twelve Weeks of Treatment, and to Assess the Safety, Tolerability, and Long-term Efficacy in Subjects From 6 to Less Than 18 Years of Age With Severe Chronic Plaque Psoriasis

This was a multicenter, randomized, double-blind, placebo- and active-controlled (etanercept in single blinded arm) study in pediatric subjects aged 6 years to less than 18 years with severe chronic plaque psoriasis. Approximately 160 subjects aged 6 years to <18 years were enrolled, of which at least 30 were 6 years to <12 years old. Subjects were enrolled at approximately 70 study sites worldwide.

The purpose of this study was to demonstrate superior efficacy of secukinumab versus placebo at Week 12, based on both PASI 75 and IGA mod 2011 0 or 1 response rates in children and adolescents aged 6 to less than 18 years with severe chronic plaque psoriasis who had inadequate control of symptoms with topical treatment, or failed to respond to or tolerate previous systemic treatment and/or UV therapy The study assessed the long term safety and tolerability of secukinumab in this pediatric age group and described the efficacy and safety of secukinumab compared to etanercept. This study provided efficacy and safety data to support the extension of label of secukinumab to include children and adolescents (6 years to <18 years) with severe chronic plaque psoriasis Two age subgroups were studied in a staggered approach within this clinical study: 12 to less than 18 years of age, and 6 to less than 12 years of age . Enrolment of children aged 6 to less than 12 years began after a favorable recommendation by an independent external Data Monitoring Committee (DMC) who reviewed data of approximately 80 adolescents. Adolescents continued to be recruited while the data from the first 80 subjects was being collected and analyzed Subjects were randomized using a 1:1:1:1 ratio into one of the treatment arms: secukinumab low dose, secukinumab high dose, etanercept or placebo. Subjects randomized to secukinumab treatment arms (high dose and low dose) received dose based on the weight category (<25 kg, 25 to <50kg, ≥50 kg). The study consisted of 5 periods: screening (up to 4 weeks), induction (of 12 weeks), maintenance (of 40 weeks), extension treatment epoch (open-label of 184 weeks) and post- treatment follow-up epoch (of 16 weeks). The screening period of up to 4 weeks was used to assess eligibility of the patients and to taper patients off prohibited medications. The Induction period is defined as randomization through Week 12. In this period, the study was both active and placebo-controlled and at its completion, the primary endpoint was assessed (Week 12). The Maintenance period is defined as Week 12 (from dosing) through Week 52. During this period, the study was active-controlled, and the objectives focused on the maintenance of the response observed at Week 12. Patients who received secukinumab or etanercept during induction continued in maintenance with the same treatment. Patients who were on placebo during induction and at Week 12 were PASI 75 non-responders were switched to either secukinumab low dose or secukinumab high dose treatment group in the Maintenance period according to their baseline randomization. At the end of the Maintenance period, all patients on secukinumab entered the Extension treatment period and continued to receive the same dose of secukinumab. The Extension treatment period was defined as Week 52 (from dosing) until Week 236. In this period, all patients were treated with secukinumab, and the purpose was the collection of long-term safety and efficacy data. Patients who participated in the Maintenance period but prematurely discontinued the study were not able to enter the Extension treatment period. Patients receiving etanercept were not eligible to enter the Extension treatment period. Instead, at Week 52, they completed an EOM visit and then entered the post-treatment Follow-up period.

Depending on weight group subject will receive per dose a) 75 mg if weighing less than 50 kg b) 150 mg if weighing 50 kg or more. Secukinumab injections (one or two per dose, depending on the weight group) will be administered subcutaneously at Randomization, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, and Placebo secukinumab at Weeks 13, 14 and 15 during the blinded phase of the study; thereafter at Week 52 and every 4 weeks during the extension treatment period until Week 232.

Depending on weight group subject will receive per dose a) 75 mg if weighing less than 25 kg b) 150 mg if weighing between 25 and less than 50 kg c) 300 mg if weighing more than 50 kg. Secukinumab injections (one or two per dose, depending on the weight group) will be administered subcutaneously at Randomization, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48, and Placebo secukinumab at Weeks 13, 14 and 15 during the blinded phase of the study; thereafter at Week 52 and every 4 weeks during the extension treatment period until Week 232.

Placebo secukinumab (one or two subcutaneous injections per dose, depending on weight group) at Randomization and Weeks 1, 2, 3 4 and 8. At Week 12, subjects in the placebo group based on their PASI 75 response status at Week 12 will proceed as follows: • PASI 75 responders will discontinue study treatment at Week 12 and enter the treatment-free follow-up period • PASI 75 non-responders will receive high dose or low dose secukinumab, according to the pre-assignment at the Randomization visit. They will receive their treatment based on the weight category(<25 kg, 25- <50kg, ≥50 kg), on Weeks 12, 13, 14, 15, and then every four weeks starting at Week 16 until Week 48 during the maintenance period; thereafter at week 52 and every 4 weeks during the extension treatment period until Week 232.

Etanercept 0.8 mg/kg of subject weight and up to a maximum of 50 mg per dose. Subcutaneous etanercept 0.8 mg/kg (one or two injections per dose) once per week, for 51 weeks administered at home (self-injected or by caregiver) or at the study site. At Wk 52 subjects in the etanercept group will move into the treatment-free follow up period and terminate the study.

Number and Percentage of Participants Achieving a 75% Improvement From Baseline in PASI Score at Week 12

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 75 represents the percentage (or number) of patients who have achieved a 75% or more reduction in their PASI score from baseline.

Number and Percentage of Participants Who Showed Investigator's Global Assessment (IGA) Mod 2011 Response of 0 or 1 at Week 12

IGA: The IGA mod 2011 scale has following different scores for the state of disease: 0: Clear, No signs of psoriasis. 1: Almost clear 2: Mild 3: Moderate 4 : Severe

Number and Percentage of Participants Achieving a 90% Improvement From Baseline in PASI Score at Week 12

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 90 represents the percentage (or number) of patients who have achieved a 90% or more reduction in their PASI score from baseline.

Number and Percentage of Participants Achieving a 50%, 100% Improvement From Baseline in PASI Score at Week 12

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 50 represents the percentage (or number) of patients who have achieved a 50% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease.

Number and Percentage of Participants Achieving a 50%, 75%, 90% or 100% Improvement From Baseline in PASI Score and IGA Mod 2011 Score of 0 or 1 up to Week 12 (Induction)

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema, Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). PASI will be assessed/calculated as per standard procedure. IGA: The IGA mod 2011 scale has following different scores for the state of disease: 0: Clear, No signs of psoriasis. 1: Almost clear 2: Mild 3: Moderate 4 : Severe

Number and Percentage of Participants Achieving a 50%, 75%, 90% or 100% Improvement From Baseline in PASI Score and IGA Mod 2011 Score of 0 or 1 Up to Week 52 (Maintenance)

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema, Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). PASI will be assessed/calculated as per standard procedure. IGA: The IGA mod 2011 scale has following different scores for the state of disease: 0: Clear, No signs of psoriasis. 1: Almost clear 2: Mild 3: Moderate 4 : Severe

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 75 represents the percentage (or number)of patients who have achieved a 75% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease.

Psoriasis Area and Severity Index (PASI):Combined assessment of lesion severity and affected area into a single score: 0 (no disease) to 72(maximal disease). Body is divided into 4 areas for scoring (head, trunk, upper limbs and lower limbs); each area is scored by itself and scores are combined for final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, Erythema,Thickening (plaque elevation, induration) & Scaling(desquamation). Scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area* area score weight of section(head: 0.1, upper limbs: 0.2 trunk: 0.3 lower limbs: 0.4). Psoriasis Area and Severity Index (PASI) will be assessed/calculated as per standard procedure. PASI 75 represents the percentage (or number)of patients who have achieved a 75% or more reduction in their PASI score from baseline. PASI 100 indicates patients who have achieved a complete resolution of all disease.

IGA: The IGA mod 2011 scale has following different scores for the state of disease: 0: Clear, No signs of psoriasis. 1: Almost clear 2: Mild 3: Moderate 4 : Severe

IGA: The IGA mod 2011 scale has following different scores for the state of disease: 0: Clear, No signs of psoriasis. 1: Almost clear 2: Mild 3: Moderate 4 : Severe

Percentage Change From Baseline in Children's Dermatology Life Quality Index (cDLQI) Score Up to Week 12 (Induction)

The CDLQI measures functional disability of subjects with dermatological disorders who are less than 18 years of age and it has been utilized as a relevant clinical measure in atopic dermatitis, as well as other dermatitis clinical trials. The CDLQI is a simple, validated, self-administered 10-item questionnaire. The instrument contains six functional scales (i.e., symptoms and feeling, leisure, school or holidays, personal relationships, sleep and treatment). The questions are based on the preceding week to permit accurate recall. For the CDLQI, each question will be answered on a 4-point Likert scale scored from 0 to 3. Seven scores will be derived from the CDLQI: the total score of each of the six dimensions as well as the total score over all items. The higher the score, the more quality of life is impaired.

Percentage Change From Baseline in Children's Dermatology Life Quality Index (cDLQI) Score Up to Week 52 (Maintenance)

The CDLQI measures functional disability of subjects with dermatological disorders who are less than 18 years of age and it has been utilized as a relevant clinical measure in atopic dermatitis, as well as other dermatitis clinical trials. The CDLQI is a simple, validated, self-administered 10-item questionnaire. The instrument contains six functional scales (i.e., symptoms and feeling, leisure, school or holidays, personal relationships, sleep and treatment). The questions are based on the preceding week to permit accurate recall. For the CDLQI, each question will be answered on a 4-point Likert scale scored from 0 to 3. Seven scores will be derived from the CDLQI: the total score of each of the six dimensions as well as the total score over all items. The higher the score, the more quality of life is impaired.

Number and Percentage of Participants Achieving a Children's DLQI Score of 0 or 1 Over Time up to Week 12 (Induction)

The CDLQI measures functional disability of subjects with dermatological disorders who are less than 18 years of age and it has been utilized as a relevant clinical measure in atopic dermatitis, as well as other dermatitis clinical trials. The CDLQI is a simple, validated, self-administered 10-item questionnaire. The instrument contains six functional scales (i.e., symptoms and feeling, leisure, school or holidays, personal relationships, sleep and treatment). The questions are based on the preceding week to permit accurate recall. For the CDLQI, each question will be answered on a 4-point Likert scale scored from 0 to 3. Seven scores will be derived from the CDLQI: the total score of each of the six dimensions as well as the total score over all items. The higher the score, the more quality of life is impaired.

Number and Percentage of Participants Achieving a Children's DLQI Score of 0 or 1 Over Time up to Week 52 (Maintenance)

The CDLQI measures functional disability of subjects with dermatological disorders who are less than 18 years of age and it has been utilized as a relevant clinical measure in atopic dermatitis, as well as other dermatitis clinical trials. The CDLQI is a simple, validated, self-administered 10-item questionnaire. The instrument contains six functional scales (i.e., symptoms and feeling, leisure, school or holidays, personal relationships, sleep and treatment). The questions are based on the preceding week to permit accurate recall. For the CDLQI, each question will be answered on a 4-point Likert scale scored from 0 to 3. Seven scores will be derived from the CDLQI: the total score of each of the six dimensions as well as the total score over all items. The higher the score, the more quality of life is impaired.

Number and Percentage of Participants With Clinically Important Reduction in Disability as Evaluated by CHAQ Questionnaire Over Time at Week 12

The CHAQ questionnaire is only done for children who in addition to psoriasis are also suffering from psoriatic arthritis. The questionnaire is completed by parent or legal guardian. It consists of multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and other "activities". The person completing the questionnaire chooses from four response categories, ranging from 'without any difficulty' to 'unable to do'. Additionally two visual analog scales (overall well-being and pain of patient) must be performed.

Number and Percentage of Participants With Clinically Important Reduction in Disability as Evaluated by CHAQ Questionnaire Over Time at Week 52

The CHAQ questionnaire is only done for children who in addition to psoriasis are also suffering from psoriatic arthritis. The questionnaire is completed by parent or legal guardian. It consists of multiple choice items concerning difficulty in performing eight common activities of daily living; dressing and grooming, arising, eating, walking, reaching, personal hygiene, gripping and other "activities". The person completing the questionnaire chooses from four response categories, ranging from 'without any difficulty' to 'unable to do'. Additionally two visual analog scales (overall well-being and pain of patient) must be performed.

Inclusion criteria: Must be 6 to less than 18 years of age at the time of randomization Plaque-type psoriasis history for at least 3 months. Severe plaque-type psoriasis meeting all of the following three criteria: PASI score of 20 or greater, Investigator's Global Assessment (IGA) score of 4 Total body surface area (BSA) affected of 10% or greater. Patient being regarded by the investigator to be a candidate for systemic therapy because of: inadequate control of symptoms with topical treatment, or failure to respond to or tolerate previous systemic treatment and/or UV therapy Exclusion criteria Current forms of psoriasis other than chronic plaque-type psoriasis (for example, pustular, erythrodermic, guttate) at randomization. Current drug-induced psoriasis. Previous use of secukinumab or any drug that targets IL-17 or IL-17 receptor. Underlying condition (including, but not limited to metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal) which in the opinion of the investigator significantly immunocompromises the subject and/or places the subject at unacceptable risk for receiving an immunomodulatory therapy History of an ongoing, chronic or recurrent infectious disease, or evidence of untreated tuberculosis. History of lymphoproliferative disease or history of malignancy of any organ system within the past 5 years. Pregnant or nursing (lactating) women. Other protocol-defined inclusion/exclusion criteria may apply.

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