Study to Demonstrate the Efficacy (Including Inhibition of Structural Damage), Safety and Tolerability up to 2 Years of Secukinumab in Active Psoriatic Arthritis

Phase 3

Completed

Conditions: Psoriatic Arthritis

Interventions: Biological: Secukinumab

Registration Number: NCT02404350

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The purpose of this study was to demonstrate efficacy including effect on inhibition of progression of structural damage, safety and tolerability up to 2 years with primary focus at Week 16 (week 24 for structural damage), to support the use of secukinumab pre-filled syringe (PFS) by subcutaneous (s.c.) self-administration with or without loading regimen in subjects with active Psoriatic Arthritis (PsA) despite current or previous NSAID, DMARD therapy and/or previous anti-TNFα therapy. Long term efficacy up to 2 years was based on signs and symptoms of joint/bone structure preservation (X-ray) and improvement in physical function measured by Health Assessment Questionnaire - Disability Index (HAQ-DI©), as well as skin and nail improvement for psoriasis signs.

Detailed Description: This multicenter study uses a randomized, double-blind, placebo-controlled, parallel-group design. A screening period (SCR) running up to 10 weeks before randomization will be used to assess subject eligibility followed by 104 weeks of treatment.

At BSL approximately 990 subjects whose eligibility is confirmed will be randomized to one of four treatment groups in 2:2:2:3 ratio:

* Group 1 - secukinumab 150 mg s.c. without loading regimen

* Group 2 - secukinumab 150 mg s.c. with loading dose regimen

* Group 3 - secukinumab 300 mg s.c. with loading dose regimen

* Group 4 - Placebo s.c. NOTE: Group 4 is split into 2 treatment arms, detailed description below. At randomization, subjects will be stratified on the basis of previous anti-TNF therapy as TNFα inhibitor naïve (TNF-naïve) or TNFα inhibitor inadequate responders (TNF-IR).

At each study treatment visit, one (for secukinumab 150 mg) or two (for secukinumab 300 mg) s.c. injections in the form of PFS will be administered, since secukinumab is available in 1.0 mL (150 mg) PFSs. Placebo to secukinumab is also available in 1.0 mL to match the active drug.

At Week 16, subjects who have been randomized to secukinumab groups at BSL (Groups 1-3) will be classified as either responders (≥20% improvement from BSL in both tender joint count (TJC) and swollen joint counts (SJC)) or non-responders (\<20% improvement from BSL TJC or SJC), however they will continue on the same treatment irrespective of their response status.

At Week 16, subjects who have been randomized to placebo at BSL (Group 4) will be classified as either responders (≥20% improvement from BSL in both TJC and SJC) or non-responders (\<20% improvement from BSL TJC or SJC):

* Subjects who are non-responders will receive either secukinumab 150 mg or 300 mg s.c. every 4 weeks starting at Week 16 (as dictated by treatment sequence assigned to these subjects at BSL).

* Subjects who are responders will continue to receive placebo every 4 weeks. Starting Week 24, these subjects will receive either secukinumab 150 mg s.c. or 300 mg s.c. every 4 weeks starting at Week 24 (as dictated by treatment sequence assigned to these subjects at BSL).

At Week 24, the assessments to address the primary objective will be performed. As described above, subjects who are still receiving placebo s.c. injection will receive either secukinumab 150 mg s.c. or 300 mg s.c. every 4 weeks starting at Week 24 (as dictated by treatment sequence assigned to these subjects at BSL).

At week 52, based on Investigator's decision, the subjects on a 150 mg dose whose signs and symptoms do not show satisfactory response have the possibility to be allocated to secukinumab 300 mg s.c.

After the Week 52 database lock and analyses have been completed, site personnel and subjects will be unblinded to the original randomized treatment (sequence) assignment at randomization. In addition, treatment will be given open-label in order to eliminate the placebo injection. The subject will continue to receive the same active dose of secukinumab as open-label treatment administered until Week 100.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 997

Inclusion 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 BSL ≥3 tender joints out of 78 and ≥3 swollen joints out of 76 (dactylitis of a digit counts as one joint each).

Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies negative at screening.
Diagnosis of active plaque psoriasis or nail changes consistent with psoriasis or a 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 who are regularly taking NSAIDs as part of their PsA therapy are required to be on a stable dose for at least 2 weeks before study randomization and should remain on a stable dose up to Week 24.
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 24.
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.
Subjects on MTX must be on folic acid supplementation at randomization.
Subjects who are on a DMARD other than MTX must discontinue the DMARD 4 weeks prior to randomization visit except for leflunomide, which has to be discontinued for 8 weeks prior to randomization unless a cholestyramine wash-out has been performed.
Subjects who have been on a TNFα inhibitor must have experienced an inadequate response to previous or current treatment with a TNFα inhibitor given at an approved dose for at least 3 months or have stopped treatment due to safety/tolerability problems after at least one administration of a TNFα inhibitor.
Subjects who have previously been treated with TNFα inhibitors (investigational or approved) will be allowed entry into study after appropriate wash-out period prior to randomization

Exclusion Criteria

Chest X-ray or chest MRI with evidence of ongoing infectious or malignant process. - Subjects taking high potency opioid analgesics.

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.
Any intramuscular or intravenous or intra-articular corticosteroid treatment within 4 weeks before randomization.
Subjects who have ever received biologic immunomodulating agents except for those targeting TNFα (investigational or approved).
Previous treatment with any cell-depleting therapies including but not limited to anti- CD20, investigational agents
Other protocol-defined exclusion criteria do apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Secukinumab 300 mg load (Group 3)	Secukinumab	Secukinumab 300 mg sc injection every week for 4 weeks followed by Secukinumab 300 mg every 4 weeks until week 100
Secukinumab 150 mg load (Group 1)	Secukinumab	Secukinumab 150 mg sc injection every week for 4 weeks followed by Secukinumab 150 mg every 4 weeks until week 100 Beginning at Week 52, for subjects whose signs and symptoms were not fully controlled, and who the investigator believed may improve further with an increase in dose, may have had the secukinumab dose increased to 300mg s.c. every 4 weeks until week 100
Placebo arm 1 (Group 4)	Secukinumab	Placebo to Secukinumab sc injection every week for 4 weeks followed by placebo to Secukinumab every 4 weeks until week 16. Non-responders will be switched to Secukinumab either 150 or 300 mg sc injection every four weeks until week 100. Responders at week 16 continued receiving placebo until week 24, then were switched to secukinumab 150 or 300 mg sc injection every 4 weeks until week 100. PLEASE NOTE: Placebo arms 1 and 2 belong to the same placebo group (group 4) Beginning at Week 52, for subjects whose signs and symptoms were not fully controlled, and who the investigator believed may improve further with an increase in dose, may have had the secukinumab dose increased to 300mg s.c. every 4 weeks.
Secukinumab 150 mg no load (Group 2)	Secukinumab	Secukinumab 150 mg sc injection every 4 weeks until week 100 Beginning at Week 52, for subjects whose signs and symptoms were not fully controlled, and who the investigator believed may improve further with an increase in dose, may have had the secukinumab dose increased to 300mg s.c. every 4 weeks.
Placebo arm 2 (Group 4)	Secukinumab	Placebo to Secukinumab sc injection every week for 4 weeks followed by placebo to Secukinumab every 4 weeks until week 16. Non-responders were switched to Secukinumab either 150 or 300 mg sc injection every four weeks until week 100. Responders at week 16 continued receiving placebo until week 24, then were switched to secukinumab 150 or 300 mg sc injection every 4 weeks until week 100. PLEASE NOTE: Placebo arms 1 and 2 belong to the same placebo group (group 4) Beginning at Week 52, for subjects whose signs and symptoms were not fully controlled, and who the investigator believed may improve further with an increase in dose, may have had the secukinumab dose increased to 300mg s.c. every 4 weeks.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Active Psoriatic Arthritis (PsA) Achieving an American College of Rheumatology Response 20 (ACR20) at Week 16	Week 16	ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement based on tender 78-joint count, swollen 76-joint count and at least 20% improvement in 3 of the following 5 measures: participant's assessment of PsA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, participant's self-assessed disability (Health Assessment Questionnaire Disability Index (HAQ-DI) score), and acute phase reactant evaluated as (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR)).

Secondary Outcome Measures

Name	Time	Method
Count and Percentage of Patients Achieving an ACR50 Response	16 weeks	ACR 50 Response is a measure based on American College of Rheumatology criteria of at least a 50% improvement in the number of tender and swollen joints, and a 50% improvement in at least 3 of the following: the patient's global assessment of disease status; the patient's assessment of pain; the patient's assessment of function measured using the Stanford Health Assessment Questionnaire the physician's global assessment of disease status; serum C-reactive protein levels.
Change From Baseline in Disease Activity Score for 28 Joints (DAS28-CRP) (Utilizing High Sensitivity C-Reactive Protein (hsCRP))	16 weeks	The improvement on secukinumab 150 mg (with or without loading regimen), or 300 mg (with loading regimen) at Week 16 compared with placebo for the disease activity assessed by the changes in Disease Activity Score for 28 joints (DAS28-CRP) (utilizing High sensitivity C-Reactive Protein (hsCRP)) relative to baseline. Scores range from 0 (no difficulty) to 3 (unable to do)
Change From Baseline to Week 24 With Secukinumab Compared With Placebo for Joint/Bone Structural Damage (Using Van Der Heijde Modified Total Sharp Score (mTSS))	Baseline, Week 24	PsA modified vdH-mTSS scoring method was used to assess bone erosion \& joint space narrowing (JSN) in hands \& feet; that included the 2nd through 5th distal interphalangeal (DIP) joints of each hand. Maximum score for erosions was 5 in joints of the hands and 10 in joints of the feet with 0=no erosions, 1=discrete erosion, 2=large erosion not passing the mid-line, and 3=large erosion passing the mid-line. JSN is: 0=normal, 1=asymmetrical or minimal narrowing up to a maximum of 25%, 2 = definite narrowing with loss of up to 50% of the normal space, 3 = definite narrowing with loss of 50-99% of the normal space, and 4 = absence of a joint space. Maximum erosion score is 320 (200 for the hands and 120 for the feet), and the max total JSN score is 208 (160 for the hands and 48 for the feet). Total radiographic score (hands \& feet combined) ranges from 0 to 528, where higher scores indicate more articular damage
Change From Baseline in HAQ-DI© Score	16 weeks	The change (within treatment) on secukinumab 150 mg (with or without loading regimen), or 300 mg (with loading regimen), at Week 16 compared with placebo for the disease activity assessed by the changes in The Health Assessment Questionnaire disability index (HAQ-DI) relative to baseline.
Count and Percentage of Patients Achieving Psoriatic Area and Severity Index 90 (PASI90) Response	16 weeks	The efficacy of secukinumab 150 mg (with or without loading regimen), or 300 mg (with loading regimen) at Week 16 compared with placebo based on the proportion of patients achieving Psoriatic Area and Severity Index 90 (PASI90) response.
Count and Percentage of Patients Achieving Psoriatic Area and Severity Index 75 (PASI75) Response	Week 16	The efficacy of secukinumab 150 mg (with or without loading regimen), or 300 mg (with loading regimen) at Week 16 compared with placebo based on the proportion of patients achieving Psoriatic Area and Severity Index 75 (PASI75) response.
Count and Percentage of Patients With Enthesitis in the Subset of Patients Who Had Enthesitis at Baseline	16 weeks	The efficacy of secukinumab pooled regimen (150 mg with or without loading regimen, and 300 mg with loading regimen) at Week 16 compared with placebo based on the proportion of patients with enthesitis in the subset of patients who had enthesitis at baseline
Count and Percentage of Participants With Dactylitis in the Subset of Patients Who Have Dactylitis at Baseline	16 weeks	The efficacy of secukinumab pooled regimen (150 mg with or without loading regimen, and 300 mg with loading regimen) at Week 16 compared with placebo based on the proportion of patients with dactylitis in the subset of patients who have dactylitis at baseline