Secukinumab in Tumor Necrosis Factor (TNF) - Inadequate Response (IR) Psoriasis Participants.

Phase 3

Completed

Conditions: Psoriasis

Interventions: Biological: Secukinumab (AIN457)

Registration Number: NCT01961609

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This study was designed to prove and quantify the hypothesis that secukinumab is effective, safe and well tolerated in the treatment of moderate to severe chronic plaque-type psoriasis in patients who are inadequate responders to anti-TNFα therapy in a United Kingdom (UK) and Republic of Ireland) specific population.

Detailed Description: There is no clear evidence or guidelines on appropriate treatment once a patient with moderate/severe psoriasis has failed to respond to anti-TNFα therapy, whether a single anti-TNFα therapy failure or multiple anti-TNFα therapy failures.

Numerous double-blind, double-dummy, randomised, parallel-group, active and placebo controlled studies have already been designed and run for the Phase III secukinumab clinical development program, in accordance with Health Authorities guidelines and feedback, including Food and Drug Administration (FDA) and European Medicines Agency (EMA). None of these specifically studied patients who have failed to respond to anti-TNFα therapy as defined by National Institute for Health and Care Excellence (NICE) guidelines.

Therefore, this study utilises a pragmatic, open-label, non-comparator design, which has been shown to be appropriate in similar studies looking at anti-TNFα therapy in patients failing on other therapies (Papp et al. 2012; Strober et al. 2011), to answer the question of whether secukinumab is an appropriate choice in patients who have failed to respond to anti-TNFα therapy (TNF-IR) per NICE definitions, whether a single anti-TNFα therapy failure or multiple anti-TNFα therapy failures.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 235

Inclusion Criteria

Written informed consent must be obtained before any assessment is performed
Aged at least 18 years at screening
Chronic plaque-type psoriasis diagnosed for at least 6 months prior to screening
Moderate to severe disease severity:
- PASI ≥10 and
- DLQI >10
Failed to respond to systemic therapies including cyclosporine and/or methotrexate and/or PUVA (or is intolerant and/or has a contraindication to these)
Previously treated with at least one anti-TNFα for moderate or severe psoriasis but is a primary or secondary non-responder
Able to communicate well with the investigator, to understand and comply with the requirements of the study.

Key

Exclusion Criteria

Forms of psoriasis other than chronic plaque-type (e.g., pustular, erythrodermic and guttate psoriasis)
Drug-induced psoriasis (i.e., new onset or current exacerbation from beta-blockers, calcium channel inhibitors or lithium)
Ongoing use of prohibited psoriasis treatments (e.g., topical or systemic corticosteroids (CS), UV therapy). Washout periods detailed in the protocol must be adhered to.
Ongoing use of other non-psoriasis prohibited treatments. Washout periods detailed in the protocol have to be adhered to. All other prior non-psoriasis concomitant treatments must be on a stable dose for at least four weeks before initiation of study drug.
Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or the IL-17 receptor
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant unless they use 2 (two) effective forms of contraception during the study and for 16 weeks after stopping treatment.
Men with a female partner of child bearing potential defined as all women physiologically capable of becoming pregnant unless they use 1 (one) effective form of contraception during the study and for 16 weeks after stopping treatment.
Active systemic infections during the last two weeks (exception: common cold) prior to initiation of study drug and any infections that reoccur on a regular basis; investigator discretion should be used regarding patients who have travelled or recently resided in areas of endemic mycoses, such as histoplasmosis, coccidioidomycosis or blastomycosis and for patients with underlying conditions that may predispose them to infection, such as advanced or poorly controlled diabetes
History of an ongoing, chronic or recurrent infectious disease, or evidence of tuberculosis infection as defined by a positive QuantiFERON TB-Gold test (QFT) at screening. Patients with a positive QFT test may participate in the study if further work up establishes conclusively that the patient has no evidence of active tuberculosis. If presence of latent tuberculosis is established, then treatment must have been initiated and maintained according to UK guidelines.
Known infection with HIV, hepatitis B or hepatitis C at screening or at initiation of study drug.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Secukinumab (AIN457) 300 mg	Secukinumab (AIN457)	Participants self-administered 300 mg secukinumab loading dose subcutaneously at Day 0 (initiation of study drug) and at weeks 1, 2, 3 \& 4, and then every 4 weeks. Following the Primary Endpoint at 16 weeks, participants meeting the NICE criteria of adequate response were eligible to continue on study treatment for a further 32 weeks. Participants not meeting this NICE criterion returned to routine treatment under the care of their usual Clinical Team. Following assessment at week 48, participants meeting the NICE criteria of adequate response were eligible to continue on study treatment for a further 24 weeks. Participants not meeting this NICE criterion returned to routine treatment under the care of their usual Clinical Team.
Secukinumab (AIN457) 150 mg	Secukinumab (AIN457)	Participants self-administered secukinumab 150 mg loading dose subcutaneously at Day 0 (initiation of study drug), weeks 1, 2, 3 \& 4 and then every 4 weeks. Following the Primary Endpoint at 16 weeks, participants meeting the NICE criteria of adequate response were eligible to continue on study treatment for a further 32 weeks at the 150mg dose. Participants not achieving the NICE criteria at the Primary Endpoint were up titrated to 300mg. Following assessment at week 48, participants meeting the NICE criteria of adequate response were eligible to continue on study treatment for a further 24 weeks at the 150mg dose. Participants not achieving the NICE criteria at 48 weeks on the 150mg dose were up titrated to 300mg.

Primary Outcome Measures

Name	Time	Method
Percentage of Secukinumab 300 mg Participants Achieving PASI 75 at 16 Weeks	16 weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving PASI 50 and PASI 90 - Maintenance 1 Period	16, 24 and 48 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 50 and PASI 90 are defined as participants achieving ≥ 50% and ≥ 90% improvement from baseline, respectively.
Percentage of Participants Achieving PASI 50 and PASI 90 - Maintenance 2 Period	48 and 72 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 50 and PASI 90 are defined as participants achieving ≥ 50% and ≥ 90% improvement from baseline, respectively.
Mean Change From Baseline in Dermatology Life Quality Index (DLQI)Total Scores - Maintenance 1 Period	Baseline, 16, 24 and 48 weeks	The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases. The measure is widely used: it has been tested across 32 different skin conditions and is available in 55 languages. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). "Not relevant" is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. A negative change from baseline indicates improvement.
Percentage of Participants Achieiving PASI 75 - Initiation Period	2 ,4, 8, 12 and 16 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.
Percentage of Secukinumab 150 mg Participants Achieving PASI 75 at 16 Weeks	16 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.
Percentage of Participants Achieving PASI 75 According to 3 Key Participant Subgroups (Primary Inadequate Response (IR), Secondary IR and IR After More Than One Anti-TNFalpha Therapies) at 16 Weeks	16 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.
Percentage of Participants Achieiving PASI 75 - Maintenance 1 Period	16, 24 and 48 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.
Mean Percent Change in EuroQOL 5-Dimension Health Status Questionnaire (EQ-5D) Health State Assessment Scores (From 0 to 100) - Initiation Period	Baseline, 12 and 16 weeks	The EQ-5D is an instrument used to assess a participant's health status. The instrument includes a descriptive profile and a visual analog scale (VAS). The descriptive profile includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 3 response levels: no problems, some problems and severe problems. The VAS is a vertical scale that assesses the health status from 0 (worst possible health state) to 100 (best possible health state). This outcome measures the percent change in VAS score.
Mean Percent Change in EuroQOL 5-Dimension Health Status Questionnaire (EQ-5D) Health State Assessment Scores (From 0 to 100) - Maintenance 1 Period	Baseline, 16, 24 and 48 weeks	The EQ-5D is an instrument used to assess a participant's health status. The instrument includes a descriptive profile and a visual analog scale (VAS). The descriptive profile includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 3 response levels: no problems, some problems and severe problems. The VAS is a vertical scale that assesses the health status from 0 (worst possible health state) to 100 (best possible health state). This outcome measures the percent change in VAS score.
Percentage of Participants Achieiving PASI 75 - Maintenance 2 Period	48 and 72 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.
Percentage of Participants Who Have Failed on One Anti-TNFα Achieving PASI 75 (Subgroups 1 and 2 Combined) at 16 Weeks	16 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 75 is defined as participants achieving ≥ 75% improvement from baseline.
Mean Change From Baseline in Dermatology Life Quality Index (DLQI) Total Scores - Initiation Period	Baseline, week 12, and week 16	The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases. The measure is widely used: it has been tested across 32 different skin conditions and is available in 55 languages. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). "Not relevant" is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. A negative change from baseline indicates improvement.
Percentage of Participants Achieving PASI 50 and PASI 90 - Initiation Period	2, 4, 8, 12, 16 Weeks	PASI is a 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, arms, trunk, legs); 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, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area\* area score weight of section (head: 0.1, arms: 0.2 body: 0.3 legs: 0.4). PASI 50 and PASI 90 are defined as participants achieving ≥ 50% and ≥ 90% improvement from baseline, respectively.
Percentage of Participants Achieving NICE Continuation Criteria (PASI 75 or PASI 50 Plus a 5 Point Improvement in DLQI) at 16 Weeks	16 Weeks	PASI 75 is defined as participants achieving ≥ 75% improvement from baseline. The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases. The measure is widely used: it has been tested across 32 different skin conditions and is available in 55 languages. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment.
Mean Change From Baseline in Dermatology Life Quality Index (DLQI)Total Scores - Maintenance 2 Period	Baseline, 48 and 72 weeks	The DLQI is a ten item general dermatology disability index designed to assess health-related quality of life in adult participants with skin diseases. The measure is widely used: it has been tested across 32 different skin conditions and is available in 55 languages. It is a self-administered questionnaire which includes domains of daily activity, leisure, personal relationships, symptoms and feelings, treatment and school/work activities. Each domain has 4 response categories ranging from 0 (not at all) to 3 (very much). "Not relevant" is a valid score also and is scored as 0. The DLQI total score is a sum of all 10 responses. Scores range from 0 to 30 with higher scores indicating greater health-related quality of life impairment. A negative change from baseline indicates improvement.
Mean Percent Change in EuroQOL 5-Dimension Health Status Questionnaire (EQ-5D) Health State Assessment Scores (From 0 to 100) - Maintenance 2 Period	Baseline, 48 and 72 weeks	The EQ-5D is an instrument used to assess a participant's health status. The instrument includes a descriptive profile and a visual analog scale (VAS). The descriptive profile includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension had 3 response levels: no problems, some problems and severe problems. The VAS is a vertical scale that assesses the health status from 0 (worst possible health state) to 100 (best possible health state). This outcome measures the percent change in VAS score.