Clinical trial NCT02404350: Study to Demonstrate the Efficacy (Including Inhibition of Structural Damage), Safety and Tolerability up to 2 Years of Secukinumab in Active Psoriatic Arthritis
Official title: A Phase III, Randomized, Double-blind, Placebo Controlled Multi-center Study of Subcutaneous Secukinumab (150 mg and 300 mg) in Prefilled Syringe to Demonstrate Efficacy (Including Inhibition of Structural Damage), Safety, and Tolerability up to 2 Years in Subjects With Active Psoriatic Arthritis (FUTURE 5)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Psoriatic Arthritis
Keywords: Psoriatic Arthritis
Arthritis
Psoriatic
Psoriatic Arthropathy
Spondylitis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2015-03-31
Enrollment: 997
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants With Active Psoriatic Arthritis (PsA) Achieving an American College of Rheumatology Response 20 (ACR20) at Week 16
timeFrame: Week 16
Secondary outcomes:
measure: 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))
timeFrame: Baseline, Week 24
measure: Count and Percentage of Patients Achieving Psoriatic Area and Severity Index 75 (PASI75) Response
timeFrame: Week 16
measure: Count and Percentage of Patients Achieving Psoriatic Area and Severity Index 90 (PASI90) Response
timeFrame: 16 weeks
measure: Count and Percentage of Patients Achieving an ACR50 Response
timeFrame: 16 weeks
measure: Change From Baseline in HAQ-DI© Score
timeFrame: 16 weeks
measure: Change From Baseline in Disease Activity Score for 28 Joints (DAS28-CRP) (Utilizing High Sensitivity C-Reactive Protein (hsCRP))
timeFrame: 16 weeks
measure: Count and Percentage of Patients With Enthesitis in the Subset of Patients Who Had Enthesitis at Baseline
timeFrame: 16 weeks
measure: Count and Percentage of Participants With Dactylitis in the Subset of Patients Who Have Dactylitis at Baseline
timeFrame: 16 weeks
Other outcomes:
Locations:
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country: United States
facility: Novartis Investigative Site
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city: Aurora
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facility: Novartis Investigative Site
state: Colorado
city: Denver
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state: Colorado
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state: Florida
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state: Idaho
city: Shreveport
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state: Louisiana
city: Brooklyn
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state: New York
city: Rochester
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facility: Novartis Investigative Site
state: New York
city: Oklahoma City
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facility: Novartis Investigative Site
state: Oklahoma
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
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facility: Novartis Investigative Site
state: Oregon
city: Duncansville
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city: Wexford
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facility: Novartis Investigative Site
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city: Wyomissing
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state: Pennsylvania
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state: Tennessee
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state: Tennessee
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facility: Novartis Investigative Site
state: Texas
city: Seattle
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facility: Novartis Investigative Site
state: Washington
city: Seattle
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facility: Novartis Investigative Site
state: Washington
city: Seattle
country: United States
facility: Novartis Investigative Site
state: Washington
city: Spokane
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facility: Novartis Investigative Site
state: Washington
city: Caba
country: Argentina
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state: Buenos Aires
city: San Miguel de Tucuman
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state: Tucuman
city: Tucuman
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city: Graz
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city: Vienna
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city: Vienna
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city: Vancouver
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state: British Columbia
city: Victoria
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state: British Columbia
city: Winnipeg
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city: Ostrava
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city: Praha 11
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city: Praha 2
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state: Czech Republic
city: Praha 4
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facility: Novartis Investigative Site
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city: Praha 4
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city: Uherske Hradiste
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city: Odense
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city: Tartu
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country: Finland
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city: Aachen
country: Germany
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city: Bad Abbach
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city: Berlin
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city: Berlin
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facility: Novartis Investigative Site
city: Germering
country: Germany
facility: Novartis Investigative Site
city: Gommern
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facility: Novartis Investigative Site
city: Gottingen
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facility: Novartis Investigative Site
city: Hamburg
country: Germany
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city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Herne
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city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Lubeck
country: Germany
facility: Novartis Investigative Site
city: Nienburg
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
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state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
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city: Athens
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city: Patras
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city: Guatemala City
country: Guatemala
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city: Guatemala City
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city: Budapest
country: Hungary
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city: Kistarcsa
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city: Szekesfehervar
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city: Veszprem
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city: Secunderabad
country: India
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state: Andhra Pradesh
city: Ahmedabad
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state: Gujarat
city: Mumbai
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country: Ireland
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state: LT
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state: LT
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country: Lithuania
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country: Russian Federation
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city: Ekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Ekaterinburg
country: Russian Federation
facility: Novartis Investigative Site
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
city: Kemerovo
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhniy Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Nizhny Novgorod
country: Russian Federation
facility: Novartis Investigative Site
city: Orenburg
country: Russian Federation
facility: Novartis Investigative Site
city: Rostov on Don
country: Russian Federation
facility: Novartis Investigative Site
city: Saint-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Smolensk
country: Russian Federation
facility: Novartis Investigative Site
city: St-Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Yaroslavl
country: Russian Federation
facility: Novartis Investigative Site
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sabadell
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Sant Joan Despi
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Alicante
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Santiago de Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: Bilbao
country: Spain
facility: Novartis Investigative Site
state: Pais Vasco
city: Vigo
country: Spain
facility: Novartis Investigative Site
state: Pontevedra
city: Baracaldo
country: Spain
facility: Novartis Investigative Site
state: Vizcaya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Bangkoknoi
country: Thailand
facility: Novartis Investigative Site
state: Bangkok
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Chiang Mai
country: Thailand
facility: Novartis Investigative Site
city: Truro
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: Christchurch
country: United Kingdom
facility: Novartis Investigative Site
state: Dorset
city: London
country: United Kingdom
facility: Novartis Investigative Site
state: England
city: Basingstoke
country: United Kingdom
facility: Novartis Investigative Site
state: Hampshire
city: Inverness
country: United Kingdom
facility: Novartis Investigative Site
state: Invernesshire
city: Salford
country: United Kingdom
facility: Novartis Investigative Site
state: Manchester
city: Stoke on Trent
country: United Kingdom
facility: Novartis Investigative Site
state: Staffordshire
city: Bradford
country: United Kingdom
facility: Novartis Investigative Site
state: West Yorkshire
city: Bath
country: United Kingdom
facility: Novartis Investigative Site
city: Dundee
country: United Kingdom
facility: Novartis Investigative Site
city: Eastbourne
country: United Kingdom
facility: Novartis Investigative Site
city: Edinburgh
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
city: Leicester
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
city: Oxford
country: United Kingdom
facility: Novartis Investigative Site
city: Portsmouth
country: United Kingdom
facility: Novartis Investigative Site
city: Wigan
country: United Kingdom
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
state: VNM
city: Hanoi
country: Vietnam
facility: Novartis Investigative Site
city: Ho Chi Minh
country: Vietnam
facility: Novartis Investigative Site
Study officials:
References:
citation: Mease P, van der Heijde D, Landewe R, Mpofu S, Rahman P, Tahir H, Singhal A, Boettcher E, Navarra S, Meiser K, Readie A, Pricop L, Abrams K. Secukinumab improves active psoriatic arthritis symptoms and inhibits radiographic progression: primary results from the randomised, double-blind, phase III FUTURE 5 study. Ann Rheum Dis. 2018 Jun;77(6):890-897. doi: 10.1136/annrheumdis-2017-212687. Epub 2018 Mar 17.
citation: Pournara E, Kormaksson M, Nash P, Ritchlin CT, Kirkham BW, Ligozio G, Pricop L, Ogdie A, Coates LC, Schett G, McInnes IB. Clinically relevant patient clusters identified by machine learning from the clinical development programme of secukinumab in psoriatic arthritis. RMD Open. 2021 Nov;7(3):e001845. doi: 10.1136/rmdopen-2021-001845.
citation: Mease PJ, Landewe R, Rahman P, Tahir H, Singhal A, Boettcher E, Navarra S, Readie A, Mpofu S, Delicha EM, Pricop L, van der Heijde D. Secukinumab provides sustained improvement in signs and symptoms and low radiographic progression in patients with psoriatic arthritis: 2-year (end-of-study) results from the FUTURE 5 study. RMD Open. 2021 Jul;7(2):e001600. doi: 10.1136/rmdopen-2021-001600.
citation: van der Heijde D, Mease PJ, Landewe RBM, Rahman P, Tahir H, Singhal A, Boettcher E, Navarra S, Zhu X, Ligozio G, Readie A, Mpofu S, Pricop L. Secukinumab provides sustained low rates of radiographic progression in psoriatic arthritis: 52-week results from a phase 3 study, FUTURE 5. Rheumatology (Oxford). 2020 Jun 1;59(6):1325-1334. doi: 10.1093/rheumatology/kez420.