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Study to Demonstrate the Efficacy, Safety and Tolerability of Intravenous Secukinumab up to 52 Weeks in Subjects With Active Psoriatic Arthritis (INVIGORATE 2)

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ClinicalTrials.gov Identifier: NCT04209205
Recruitment Status : Completed
First Posted : December 24, 2019
Results First Posted : April 26, 2024
Last Update Posted : April 26, 2024
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE October 30, 2019
First Posted Date  ICMJE December 24, 2019
Results First Submitted Date  ICMJE May 8, 2023
Results First Posted Date  ICMJE April 26, 2024
Last Update Posted Date April 26, 2024
Actual Study Start Date  ICMJE January 29, 2020
Actual Primary Completion Date May 17, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 30, 2023)
Percentage of Participants With American College of Rheumatology 50 (ACR50) Response Comparison Between Treatment Groups Using Non-responder Imputation at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
Percentage of participants with active psoriatic arthritis (PsA) who achieved 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)
Original Primary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
Proportion of subjects achieving American College of Rheumatology 50 (ACR50) response criteria [ Time Frame: Week 16 ]
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)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2023)
  • Percentage of Participants With American College of Rheumatology 20 (ACR20) Response Comparison Between Treatment Groups Using On-responder Imputation at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein.
  • Percentage of Participants With Minimal Disease Activity (MDA 5/7) Comparison Between Treatment Groups Using On-responder Imputation at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    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
  • Percentage of Participants With Psoriasis Area and Severity Index 90 (PASi90) Score for Patients With a >= 3% Body Surface Area Psoriasis at Baseline Using On-responder Imputation at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    Change from baseline of a 90% reduction in the PASI score for patients with a >= 3% body surface area psoriasis at baseline. Four body surface areas are evaluated (head, trunk and upper and lower limbs) for plaque, erythema, scaling and thickness. The degree of severity of each sign in each of the 4 body areas was assigned a score of 0 to 4. Scores ranged from 0 to 72 and higher scores represent worsening severity.
  • Psoriatic Arthritis Disease Activity Score (PASDAS) Change From Baseline Using Mixed Model Repeated Measures (MMRM) at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    PASDAS is a composite measure developed to assess disease activity in Psoriatic arthritis. It is calculated by utilizing seven measures: Patient reported measures (excluding mental component) (SF-36-PCS), skin, peripheral joint counts (tender and swollen joint counts), dactylitis (LDI), enthesitis (LEI), acute phase response (CRP), and patient and physician global VAS scores. The typical score range is between 0 and 10. Smaller values on PASDAS indicate a better condition; a negative change from baseline indicates improvement.
  • Health Assessment Questionnaire - Disability Index (HAQ-DI) Score Change From Baseline Using Mixed Model Repeated Measures (MMRM) at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability.
  • Short Form 36-Physical Component Summary (SF36-PCS) Score Change From Baseline Using Mixed Model Repeated Measures (MMRM) at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    The SF-36 is used to measure health-related quality of life with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Range of scoring is 0 -100, with higher scores indicating better health status.
  • Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score Change From Baseline Using Mixed Model Repeated Measures (MMRM) at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    The FACIT-Fatigue is a 13 item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. Response scale ranges from 0-4 and the total score range is 0 - 52. Higher scores indicate better quality of life
  • Modified Nail Psoriasis Severity Index (mNAPSI) Score Change From Baseline Using Mixed Model Repeated Measures (MMRM) at Week 16 (Full Analysis Set) [ Time Frame: Baseline up to Week 16 ]
    The mNAPSI is an instrument to assess psoriatic nail involvement. Three groups of features (onycholysis and oil-drop dyshromia, pitting and crumbling) were graded on a scale from 0 to 3 for a total subscale of 0 to 9. The next 4 abnormalities (leukonychia, splinter hemorrhages, hyperkeratosis and red spots in the lunula) were graded as absent (0) or present (1) for a total subscale of 0 to 4. The total score was from 0-13 where higher scores represent worse nail disease.
  • Percentage of Participants With Complete Resolution of Dactylitis at Week 16 Using Non-responder Imputation (Dactylitis Subset) [ Time Frame: Baseline up to Week 16 ]
    Dactylitis is characterized by swelling of the entire finger or toe. The Leeds Dactylitis Index (LDI) measures the ratio of the circumference of the affected (swollen) digit. The ratio of circumference is multiplied by a tenderness score, using a modification of LDI that is a binary score (1 for tender, 0 for non-tender). The LDI requires a finger circumference gauge or a dactylometer to measure digital circumference. Scores range from 0 - 20 and lower score indicates better outcome.
  • Percentage of Participants With Complete Resolution of Enthesitis at Week 16 Using Non-responder Imputation (Enthesitis Subset (LEI)) [ Time Frame: Baseline up to Week 16 ]
    Enthesitis is inflammation of the enthesis which is where a a tendon or ligament attaches to the bone. The Leeds enthesitis index (LEI) is a validated index that uses 6 sites for evaluation of enthesitis: lateral epicondyle humerus L + R, proximal achilles L + R and medial condyle femur L+R. If enthesitis is present at any of the 6 sites, the subject is counted as a subject with enthesitis.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • Proportion of subjects achieving American College of Rheumatology 20 (ACR20) response [ Time Frame: Week 16 ]
    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)
  • Proportion of patients achieving Minimal Disease Activity (MDA) 5/7 [ Time Frame: Week 16 ]
    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
  • Proportion of subjects achieving a Psoriasis Area and Severity Index 90 (PASI90) response [ Time Frame: Week 16 ]
    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
  • Change from baseline for the PsA Disease Activity Score (PASDAS) [ Time Frame: Week 16 ]
    Change from baseline for PASDAS (Range: 0-10), with higher scores indicating worse disease activity
  • Change from baseline for the Health Assessment Questionnaire - Disability Index (HAQ-DI) [ Time Frame: Week 16 ]
    Change from baseline for HAQ-DI (Range: 0-3). Higher scores indicate severe disability
  • Change from baseline for the Short Form 36-Physical Component Summary (SF36-PCS) [ Time Frame: Week 16 ]
    Change from baseline for SF36-PCS (Range: 0-100), with higher scores indicating better health status.
  • Change from baseline for the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) [ Time Frame: Week 16 ]
    Change from baseline for FACIT-F on 0-4 response scale. Range: 0-52. Higher scores indicate better quality of life
  • Change from baseline for the Modified Nail Psoriasis Severity Index (mNAPSI) [ Time Frame: Week 16 ]
    7 groups of features for each fingernail (Score: 0-130). Higher scores represent worse nail disease
  • Proportion of subjects with dactylitis in the subset of subjects who have dactylitis at baseline [ Time Frame: Week 16 ]
    Finger size and tenderness (Range 0-20). A higher score implies worse dactylitis
  • Proportion of subjects with enthesitis in the subset of subjects who have enthesitis at baseline [ Time Frame: Week 16 ]
    6 enthesial sites and tenderness (Range: 0 -6). Higher count implies greater enthesitis burden
  • Assessment of safety and tolerability of i.v. secukinumab compared to placebo [ Time Frame: Week 16 ]
    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)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Demonstrate the Efficacy, Safety and Tolerability of Intravenous Secukinumab up to 52 Weeks in Subjects With Active Psoriatic Arthritis
Official Title  ICMJE 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
Brief Summary 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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

This was a double-blind, randomized treatment trial.

Subjects, investigator staff, persons performing the assessments remained blinded to the identity of the treatment from the time of randomization until Week 60 database lock, using the following methods:

  1. Randomization data were kept strictly confidential until the time of unblinding and were not accessible by anyone else involved in the study with the exception of the bioanalyst.
  2. The identity of the treatments were concealed by the use of study treatments in the form of i.v. injection, filled with secukinumab or placebo that were identical in appearance.
Primary Purpose: Treatment
Condition  ICMJE Psoriatic Arthritis
Intervention  ICMJE
  • Drug: AIN457 6 mg/kg i.v.
    AIN457 6 mg/kg delivered by i.v. infusion
    Other Name: secukinumab
  • Drug: Placebo
    Matching placebo to AIN457 i.v. infusion
  • Drug: AIN457 3 mg/kg
    AIN457 3 mg/kg delivered by i.v. infusion
    Other Name: secukinumab
Study Arms  ICMJE
  • Experimental: AIN457 6 mg/kg - 3 mg/kg i.v.
    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).
    Interventions:
    • Drug: AIN457 6 mg/kg i.v.
    • Drug: AIN457 3 mg/kg
  • Placebo Comparator: Placebo
    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).
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 19, 2022)
381
Original Estimated Enrollment  ICMJE
 (submitted: December 19, 2019)
380
Actual Study Completion Date  ICMJE May 17, 2022
Actual Primary Completion Date May 17, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Brazil,   Bulgaria,   Colombia,   Czechia,   Greece,   Guatemala,   India,   Malaysia,   Philippines,   Poland,   Russian Federation,   South Africa,   Thailand,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04209205
Other Study ID Numbers  ICMJE CAIN457P12302
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Current Responsible Party Novartis ( Novartis Pharmaceuticals )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Novartis Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Novartis
Verification Date August 2023

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP