Efficacy at 24 Weeks With Long Term Safety, Tolerability and Efficacy up to 5 Years of Secukinumab in Patients of Active Psoriatic Arthritis

Phase 3

Completed

Conditions: Psoriatic Arthritis

Interventions: Drug: Secukinumab (AIN457)
Drug: Placebo

Registration Number: NCT01752634

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: This study was to provide 24 - 52 week efficacy, safety and tolerability data to support the registration of the secukinumab (AIN457) prefilled syringe (PFS) for subcutaneous self administration in subjects with active PsA despite current or previous NSAID, DMARD and/or anti-TNFα therapy. An additional 4 years of long-term efficacy and safety data were collected during the post Week 52 period of the study.

Detailed Description: At baseline (BSL), subjects whose eligibility was confirmed were randomized to one of the following four treatment groups.

* 75 mg secukinumab

* 150 mg secukinumab

* 300 mg secukinumab

* Placebo At Week 16, all subjects were classified as responders (≥ 20% improvement from BSL in both tender and swollen joint counts) or non-responders.

Subjects who were randomized to a secukinumab treatment group at baseline were targeted to remain on the same dose for the entire trial.

Subjects who were randomized to placebo at baseline were re-randomized at Week 16 as follows:

Placebo non-responders received secukinumab 150 mg s.c. or 300 mg s.c. (1:1) every 4 weeks, starting after the efficacy assessments at Week 16.

Placebo responders continued to receive placebo at Week 16 and Week 20 and received secukinumab 150 mg s.c. or 300 mg s.c. (1:1) every 4 weeks, starting after the efficacy assessments at Week 24.

This was a double-blind, double-dummy, randomized treatment trial until week 52 analysis was completed and open label afterwards.

An amendment to the study protocol (after all patients were in the trial for 2-3 years) introduced changes whereby patients previously treated with secukinumab 75 mg s.c. could change to receive 150 mg s.c. or 300 mg s.c., and patients previously treated with secukinumab 150 mg s.c. could change to receive 300 mg s.c., as deemed appropriate by the investigators.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 397

Inclusion Criteria

Patients eligible for inclusion in this study have 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 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.

Exclusion Criteria

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, scalp and genital area during screening, only corticosteroids with mild to moderate potency) 2 weeks
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 (e.g., CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Secukinumab (AIN457) 300 mg s.c.	Secukinumab (AIN457)	Secukinumab 300 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4
Placebo s.c.	Secukinumab (AIN457)	Placebo at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4. Non-responder (assessed at Week 16) were re-randomized to receive AIN457 150mg or AIN457 300 mg starting at Week 16. Responder (assessed at Week 16) were re-randomized to receive AIN457 150mg or AIN457 300 mg starting at Week 24.
Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457)	Secukinumab 75 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4.
Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457)	Secukinumab 150 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4.
Placebo s.c.	Placebo	Placebo at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4. Non-responder (assessed at Week 16) were re-randomized to receive AIN457 150mg or AIN457 300 mg starting at Week 16. Responder (assessed at Week 16) were re-randomized to receive AIN457 150mg or AIN457 300 mg starting at Week 24.

Primary Outcome Measures

Name	Time	Method
Number of Participants Achieving American College of Rheumatology 20 (ACR20) Response Criteria	Week 24	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 in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). For subjects with early escape at Week 16 or had missing values at Week 24 or discontinued prior to Week 24, their ACR20 was set to nonresponse at Week 24. This applied for all treatment regimens in order to minimize bias. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Achieving a PASI75 Response in the Subgroup of Subjects Who Have ≥3% Skin Involvement With Psoriasis	Week 24	PASI is a combined assessment of a lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). The body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for a 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 response was defined as participants achieving \>= 75% improvement from baseline. For subjects with early escape at Week 16 or had missing values at Week 24 or discontinued prior to Week 24, their value was set to nonresponse at Week 24. This applied for all treatment regimens in order to minimize bias.
Number of Participants Achieving a PASI90 Response in the Subgroup of Subjects Who Have ≥3% Skin Involvement With Psoriasis	Week 24	PASI is a combined assessment of a lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). The body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for a 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 90 response was defined as participants achieving \>= 90% improvement from baseline. For subjects with early escape at Week 16 or had missing values at Week 24 or discontinued prior to Week 24, their value was set to nonresponse at Week 24. This applied for all treatment regimens in order to minimize bias.
Change From Baseline in DAS28-CRP	Baseline, Week 24	The DAS28 is a measure of disease activity based on Swollen and Tender Joint Counts, ESR or CRP and the Patient Global Assessment. A DAS28 score \> 5.1 implies active disease, ≤ 3.2 low disease activity, and \< 2.6 remission. The score can range from 0 - 9.4. The data collected after the patient switched to secukinumab were treated as missing for placebo patients and were analyzed using a mixed-effects repeated measures model. For secukinumab patients, the actual values were used in the analysis. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.
Change From Baseline in SF36-Physical Component Score	Baseline, Week 24	The SF-36 is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions. Score range is from 0 (no problems) to 100 (unable to perform the activity). SF-36 is a 36 item questionnaire which measures Quality of Life across eight domains, which are both physically and emotionally based. Two overall summary scores, the Physical Component Summary (PCS) and Mental Component Summary (MCS) can be computed. In this study, SF-36 PCS was used. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.
Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)	Baseline, Week 24	The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, "are you able to..." perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.
Number of Participants Achieving American College of Rheumatology 50 (ACR50) Response Criteria	Week 24	ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 50% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient's assessment of RA pain, patient's global assessment of disease activity, physician's global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire \[HAQ-DI\] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). For subjects with early escape at Week 16 or had missing values at Week 24 or discontinued prior to Week 24, their ACR20 was set to nonresponse at Week 24. This applied for all treatment regimens in order to minimize bias. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.
Number of Participants With Dactylitis in the Subset of Subjects Who Had Dactylitis at Baseline	Week 24	Resolution of dactylitis was evaluated in the subset of patients who had disease activity at baseline. In this analysis, a lower percentage is desirable and resolution is defined as complete absence of the symptom. For subjects with early escape at Week 16 or had missing values at Week 24 or discontinued prior to Week 24, their assessment was set to nonresponse at Week 24 (presence of dactylitis). This applied for all treatment regimens in order to minimize bias. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.
Number of Participants With Enthesitis in the Subset of Subjects Who Had Enthesitis at Baseline	Week 24	Resolution of enthesitis was evaluated in the subset of patients who had disease activity at baseline. In this analysis, a lower percentage is desirable and resolution is defined as complete absence of the symptom. For subjects with early escape at Week 16 or had missing values at Week 24 or discontinued prior to Week 24, their assessment was set to nonresponse at Week 24 (presence of enthesitis). This applied for all treatment regimens in order to minimize bias. The Placebo arm was analyzed as one group, irrespective of the re-randomization, as assessments made under the re-randomized active treatment were not included in this analysis.