Study to Demonstrate the Efficacy, Safety and Tolerability of Intravenous Secukinumab up to 52 Weeks in Subjects With Active Psoriatic Arthritis

Study Overview
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Brief Summary
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The purpose of this study was to provide up to 52 weeks of efficacy, safety and tolerability data to support registration of intravenous (i.v.) secukinumab (Initial dose of 6 mg/kg at Baseline (BSL) followed thereafter with 3 mg/kg administered every four weeks) in patients with active psoriatic arthritis (PsA) despite current or previous Non-steroidal anti-inflammatory drugs (NSAIDs), Disease-modifying antirheumatic drugs (DMARDs) and/or anti-tumor necrosis factor (TNF) therapy.

Detailed Description
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This multicenter study used a randomized, double-blind, placebo-controlled, parallel-group design. A screening (SCR) period running up to 10 weeks before randomization was used to assess subject eligibility followed by a treatment period of 52 weeks. At baseline, 381 patients with active psoriatic arthritis were randomized to one of the two treatment groups in a 1:1 randomization: Group 1: Approximately 190 patients with active psoriatic arthritis; These patients received secukinumab 6 mg/kg i.v. at BSL, followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 4. Group 2: Approximately 190 patients with active psoriatic arthritis; These patients received i.v. placebo at BSL and at Weeks 4, 8, and 12, followed by the administration of secukinumab 3 mg/kg i.v. every four weeks starting at Week 16. Study consisted of 4 periods: a screening period (up to 10 weeks), treatment period 1 (total duration of 16 weeks) and treatment period 2 (total duration of 36 weeks) followed by a safety follow up period of 8 weeks after the end of treatment visit (i.e., Week 52). Primary endpoint analysis will be performed with Week 16 data (last patient completing Treatment period 1 (Week 16). Long-term efficacy and safety assessments will be performed up to Week 52.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel Group, Phase III Multicenter Study of Intravenous Secukinumab to Compare Efficacy at 16 Weeks With Placebo and to Assess Safety and Tolerability up to 52 Weeks in Subjects With Active Psoriatic Arthritis

Conditions
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Psoriatic Arthritis

Intervention / Treatment
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* Drug: AIN457 6 mg/kg i.v.
* Drug: Placebo
* Drug: AIN457 3 mg/kg


Participation Criteria
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Eligibility Criteria
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Patients eligible for inclusion in this study had to fulfill all of the following criteria: Diagnosis of PsA classified by CASPAR criteria and with symptoms for at least 6 months with moderate to severe PsA who must have at Baseline ≥3 tender joints out of 78 and ≥3 swollen out of 76 (dactylitis of a digit counts as one joint each) Rheumatoid factor and anti-CCP antibodies negative at screening Diagnosis of active plaque psoriasis or nail changes consistent with psoriasis or documented history of plaque psoriasis Subjects with PsA should have taken NSAIDs for at least 4 weeks prior to randomization with inadequate control of symptoms or at least one dose if stopped due to intolerance to NSAIDs Subjects taking corticosteroids must be on a stable dose of ≤10 mg/day prednisone or equivalent for at least 2 weeks before randomization and should remain on a stable dose up to Week 16 Subjects taking MTX (≤ 25 mg/week) are allowed to continue their medication if the dose is stable for at least 4 weeks before randomization and should remain on a stable dose up to Week 52. Patients fulfilling any of the following criteria are not eligible for inclusion in this study: Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process, obtained within 3 months prior to screening and evaluated by a qualified physician Subjects taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine) Previous exposure to secukinumab or other biologic drug directly targeting IL-17 or IL-17 receptor Ongoing use of prohibited psoriasis treatments / medications (e.g., topical corticosteroids, UV therapy) at randomization. The following wash-out periods need to be observed: Oral or topical retinoids- 4 weeks Photochemotherapy (e.g. PUVA)- 4 weeks Phototherapy (UVA or UVB)- 2 weeks Topical skin treatments (except in face, eyes, scalp and genital area during screening, only corticosteroids with mild to moderate potency)- 2 weeks Any intramuscular or intravenous corticosteroid treatment within 4 weeks before randomization. Any therapy by intra-articular injections (e.g. corticosteroid) within 4 weeks before randomization. Subjects who have previously been treated with more than 3 different TNF inhibitors (investigational or approved). Subjects who have ever received biologic immunomodulating agents, investigational or approved except for those targeting TNFα. Previous treatment with any cell-depleting therapies including but not limited to anti-CD20 or investigational agents (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: AIN457 6 mg/kg - 3 mg/kg i.v.<br>AIN457 6 mg/kg i.v. infusion at baseline, followed by AIN457 3 mg/kg i.v. infusion every 4 weeks starting at Week 4 through Week 48 (exposure through Week 52). | Drug: AIN457 6 mg/kg i.v.<br>* AIN457 6 mg/kg delivered by i.v. infusion<br>* Other names: secukinumab;Drug: AIN457 3 mg/kg<br>* AIN457 3 mg/kg delivered by i.v. infusion<br>* Other names: secukinumab;|
| Placebo Comparator: Placebo<br>Matching placebo from baseline to Week 16 and switch to AIN457 3mg/kg i.v. infusion every 4 weeks through Week 48 (exposure through Week 52). | Drug: Placebo<br>* Matching placebo to AIN457 i.v. infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving American College of Rheumatology 50 (ACR50) response criteria | To demonstrate that the efficacy of i.v. secukinumab at Week 16 is superior to placebo in subjects with active psoriatic arthritis (PsA) based on the proportion of patients achieving an American College of Rheumatology 50 (ACR50) response The ACR50 is a composite measure defined as both improvement of 50% in the number of tender and number of swollen joints, and a 50% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP) | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects achieving American College of Rheumatology 20 (ACR20) response | Improvement of ≥ 20% in tender and swollen joint count and ≥3 units in at least 3 of 5 domains as described in ACR50. The ACR20 is a composite measure defined as both improvement of 20% in the number of tender and number of swollen joints, and a 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, functional ability measure [most often Health Assessment Questionnaire (HAQ)], visual analog pain scale, and erythrocyte sedimentation rate or C-reactive protein (CRP) | Week 16 | 
| Proportion of patients achieving Minimal Disease Activity (MDA) 5/7 | MDA is assessed as 5 of the 7 following: ≤ 1 tender and swollen joint; entheseal count, PASI ≤ 1 or BSA ≤3%, PsA ≤ 15 and disease activity ≤ 20 (VAS) and HAQ-DI© ≤ 0.5 | Week 16 | 
| Proportion of subjects achieving a Psoriasis Area and Severity Index 90 (PASI90) response | Change from baseline for PASI90, 4 items measured in 4 body areas to reflect psoriasis lesional burden (Range 0-72). Higher scores represent worsening severity | Week 16 | 
| Change from baseline for the PsA Disease Activity Score (PASDAS) | Change from baseline for PASDAS (Range: 0-10), with higher scores indicating worse disease activity | Week 16 | 
| Change from baseline for the Health Assessment Questionnaire - Disability Index (HAQ-DI) | Change from baseline for HAQ-DI (Range: 0-3). Higher scores indicate severe disability | Week 16 | 
| Change from baseline for the Short Form 36-Physical Component Summary (SF36-PCS) | Change from baseline for SF36-PCS (Range: 0-100), with higher scores indicating better health status. | Week 16 | 
| Change from baseline for the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) | Change from baseline for FACIT-F on 0-4 response scale. Range: 0-52. Higher scores indicate better quality of life | Week 16 | 
| Change from baseline for the Modified Nail Psoriasis Severity Index (mNAPSI) | 7 groups of features for each fingernail (Score: 0-130). Higher scores represent worse nail disease | Week 16 | 
| Proportion of subjects with dactylitis in the subset of subjects who have dactylitis at baseline | Finger size and tenderness (Range 0-20). A higher score implies worse dactylitis | Week 16 | 
| Proportion of subjects with enthesitis in the subset of subjects who have enthesitis at baseline | 6 enthesial sites and tenderness (Range: 0 -6). Higher count implies greater enthesitis burden | Week 16 | 
| Assessment of safety and tolerability of i.v. secukinumab compared to placebo | The incidence of clinically significant abnormal laboratory values/test results and adverse, serious adverse events (by review of values outside clinically notable ranges, significant changes from Baseline or the previous visit, or values, which are considered to be non-typical in participants with underlying disease) | Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Active Psoriatic Arthritis, Intravenous secukinumab, PsA