A 24-week, Multicenter, proSpective stUdy to Evaluate the PASI 90 Clinical Response Rate and the Safety PRofile of sEcukinuMab 300 mg in Cw6-negativE and Cw6-positive Patients With Moderate to Severe Chronic Plaque-type Psoriasis (SUPREME)

Study Overview
=================
Brief Summary
-----------------
A study to evaluate the differences in the efficacy and safety of secukinumab between Cw6-negative and Cw6-positive patients with moderate to severe plaque-type psoriasis

Detailed Description
-----------------
Biological agents represent the most advanced type of treatment for psoriasis. Secukinumab is a human monoclonal anti IL-17A antibody that binds to human IL-17A and neutralizes its bioactivity by inhibiting IL17A produced by both Th17 cells and those of the innate immune system, thus providing complete anti IL17A blockage. Targeting IL-17A has the potential to reduce autoimmune inflammation while leaving other immune functions undisturbed. While targeting of Th1-promoting or Th17-promoting cytokines affects critical mediators such as IFN-γ, IL-22 and IL-21, selective targeting of IL-17A leaves these Th1/17 activities, as well as certain protective functions of innate cells intact. Furthermore, as a fully human monoclonal antibody, secukinumab should reduce immunogenic risks compared to current or emerging antibody therapies that are not fully human. Many recent studies have shown that highly selective biologic drugs are not effective in every patient and that variations in the genome can be associated with different clinical responses or side effects to a given drug. The PSORS1 locus on chromosome 6p is generally understood to confer the most risk for psoriasis. A specific allele for this locus, HLA C*06, is present in about 60% of psoriatic patient cases. Data linking secukinumab efficacy to a particular genetic marker are lacking. Recent research has revealed a marked difference in the proportion of PASI 90 achievers at 12 weeks between Cw6-positive and Cw6-negative patients (85.7% vs 56.5%) treated with ustekinumab (Talamonti M et al. 2013) and a greater efficacy of anti-TNFα drugs in CW6 negative patients (Galli et al. 2013).Unlike anti-IL-12/23 agents, secukinumab inhibits IL-17 produced by both Th17 cells after presentation by antigen presenting cells (in this case Cw6) and cells of the innate immune system whose activation does not require antigen presentation. Providing a drug that is equally effective on both Cw6-negative and Cw6-positive patients would be an important clinical accomplishment and would eliminate the need for costly HLA-Cw6 tests. The choice of a cohort study would therefore seem appropriate for this clinical context. The purpose of this study was to explore the different efficacy and safety profile of secukinumab 300 mg in patients with moderate to severe chronic plaque-type psoriasis, stratified for the presence of HLA-C*06, whose determination was blinded for patients and investigators. The study was conducted both on anti-TNFα-naïve and anti-TNFα failure patients and also stratified for TNFα - 308 polymorphism, BMI, smoking and metabolic syndrome, among others.

Official Title
-----------------
A 24-week, Multicenter, proSpective stUdy to Evaluate the PASI 90 Clinical Response Rate and the Safety PRofile of sEcukinuMab 300 mg in Cw6-negativE and Cw6-positive Patients With Moderate to Severe Chronic Plaque-type Psoriasis (SUPREME)

Conditions
-----------------
Plaque Type Psorisis

Intervention / Treatment
-----------------
* Biological: Secukinumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must have been able to understand and communicate with the investigator and to comply with the requirements of the study and must have given a written, signed and dated informed consent before any study related activity was performed. Men or women at least 18 years of age at time of screening. Diagnosis of moderate to severe chronic plaque-type psoriasis for at least 6 months (including concomitant psoriatic arthritis as per the Classification Criteria for Psoriatic Arthritis criteria [CASPAR]). Moderate to severe psoriasis as defined at enrollment by: PASI score ≥ 10 or PASI score > 5 but < 10 and DLQI ≥10 Patients that are candidates for systemic therapy, whether treatment naïve or after failed response to other systemic therapy (i.e. cyclosporine, methotrexate and PUVA) or to an anti-TNFα (or is intolerant and/or has a contraindication to these). Exclusion criteria Forms of psoriasis other than chronic plaque-type (e.g., pustular, erythrodermic and guttate psoriasis). Cyclosporine or methotrexate therapy within 4 weeks prior to Day 1. Anti-TNFα therapy within timelines depending on drug half-life. Previous exposure to secukinumab or any other biologic drug directly targeting IL-17 or the IL-17 receptor. Previous exposure to ustekinumab or any other biologic drug for the treatment of psoriasis that was not anti-TNFα therapy. Intravenous or intramuscular steroids within 2 weeks prior to screening and during screening. Ongoing use of corticosteroid topical treatments or UV therapy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arms represent stratification of Cw6 positive and Cw6 negative patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cw6-positive AIN457 300 mg<br>Stratified to Cw6 positive cohort. Investigators and patients were blinded to Cw6 results. All patients were treated according to an induction regimen of two injections of secukinumab 150 mg a week for five weeks starting at baseline (week 0), followed by a maintenance period of two injections per month. At week 16, patients achieving PASI 50 response were eligible to continue on secukinumab for an additional 8 weeks in CORE. Eligible patients with at least a PASI 75 response were included in the extension phase, up to 72 weeks | Biological: Secukinumab<br>* Secukinumab was supplied as 150 mg solution in pre-filled syringe for subcutaneous injection<br>* Other names: AIN457;|
| Experimental: Cw6-negative AIN457 300 mg<br>Stratified to Cw6 negative cohort. Investigators and patients were blinded to Cw6 results. All patients were treated according to an induction regimen of two injections of secukinumab 150 mg a week for five weeks starting at baseline (week 0), followed by a maintenance period of two injections per month. At week 16, patients achieving PASI 50 response were eligible to continue on secukinumab for an additional 8 weeks in CORE. Eligible patients with at least a PASI 75 response were included in the extension phase, up to 72 weeks | Biological: Secukinumab<br>* Secukinumab was supplied as 150 mg solution in pre-filled syringe for subcutaneous injection<br>* Other names: AIN457;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage (%) of Patients Who Reach Psoriasis Area Severity Index (PASI) 90 at 16 Weeks - LOCF Approach (ITT Set) | PASI (Langley et al 2015) combines the assessment of the severity of lesions and the area affected into a single score with a range of 0 (no disease) to 72 (maximal disease). The PASI was assessed at all visits in CORE and extension phases. PASI 90 response: patients achieving ≥ 90% improvement (reduction) in PASI score compared to baseline are defined as PASI 90 responders. | Baseline up to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage (%) of Patients With IGA 0/1, PASI 50, PASI 75, PASI 90, PASI 100 Responders by Visit - LOCF Approach (ITT Set) | IGA mod 2011 scale measures severity of the psoriasis on a five-point scale ranging from 0 (no disease, 'clear') to 4 ('very severe'). PASI 50,75,90,100 represent: patients achieving ≥ 50% improvement (reduction) in PASI score compared to baseline, ≥ 75% improvement (reduction), ≥ 90% improvement (reduction) and PASI 100 response/remission: complete clearing of psoriasis (PASI=0). | Baseline up to approximately 72 weeks | 
| Percent Mean Changes From Baseline in IGA Mod 2011 Between Cohorts at Each Time Point (LOCF) (ITT) | IGA mod 2011 scale measures severity of the psoriasis on a five-point scale ranging from 0 (no disease, 'clear') to 4 ('very severe'). | Baseline up to approximately 72 weeks | 
| Median Time to Reach PASI 90 and 75 (ITT) | Time in days to reach PASI scores of 90 and 75. | Baseline up to approximately 72 weeks | 
| Change From Baseline in the Dermatology Life Quality Index (DLQI) (LOCF) (FAS) | The DLQI total score was calculated by summing the score of each domain resulting in a maximum of 30 and a minimum of 0. The higher the score, the more Quality of Life was impaired. Meaning of DLQI Scores: 0-1 = no effect at all on patient's life, 2-5 = small effect on patient's life, 6-10 = moderate effect on patient's life, 11-20= very large effect on patient's life, 21-30 = extremely large effect on patient's life. It was pre-specified that results would be presented for all patients, not by cohort | Baseline up to approximatly 72 weeks | 
| Change From Baseline in Mean Scores of HAD-A and HAD-D (Anxiety and Depression) (LOCF) (FAS) | The Hospital Anxiety and Depression Scale (HADS) is a fourteen-item scale.. Seven of the items relate to anxiety and seven relate to depression. This outcome measure was specifically developed to avoid reliance on aspects of these conditions that are also common somatic symptoms of illness, for example fatigue and insomnia or hypersomnia. Calculations of scores: each of the 14 items was rated on a 4-point scale. All items except 7 and 10 were scored as Yes, definitely = 3, Yes, sometimes = 2, No, not much = 1, to No, not at all = 0. Items 7 and 10 were scored as Yes, definitely = 0 to No, not at all = 3 in the reverse order. The HADS consisted of two sub-scores: the HAD-A (anxiety) and HAD-D (depression); each sub-score ranged from 0 to 21 points; scores ≥11 = presence of anxious or depressive disorders; scores between 8-10 points = borderline abnormal, and scores of ≤7 = disorder was not present. It was pre-specified that results would be presented for all patients, not by cohort | Baseline up approximately 72 weeks | 
| Correlation Between the Hospital Anxiety and Depression Scale (HADS) and PASI (FAS) | PASI score, HADS questionnaire correlation using Spearman rank correlation coefficient. It was pre-specified that results would be presented for all patients, not by cohort | Baseline up to approximately 72 weeks | 
| Changes From Baseline in Body Mass Index (Safety Set) | Change in Body mass index from baseline for patients with a value at baseline and the respective post-baseline visit | Baseline up to approximately 72 weeks | 
| Changes From Baseline in Waist Circumference (Safety Set) | Change in waist circumference from baseline for patients with a value at baseline and the respective post-baseline visit | Baseline up to approximately 72 weeks | 
| Changes From Baseline in Weight (Safety Set) | Change in weight from baseline for patients with a value at baseline and the respective post-baseline visit | Baseline up to approximately 72 weeks |