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Biologic Tapering Study of TNF Inhibitors in Axial Spondyloarthritis (BIOTAPE)

Primary Purpose

Axial Spondyloarthritis

Status
Recruiting
Phase
Phase 4
Locations
Canada
Study Type
Interventional
Intervention
Tapered doses of TNFi
Standard dose of TNFi
Sponsored by
University Health Network, Toronto
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Axial Spondyloarthritis focused on measuring spondyloarthritis, TNF inhibitors, tapering

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult axSpA patients satisfying the 2009 Assessment of SpondyloArthritis International Society (ASAS) Classification Criteria
  • Currently enrolled in the SPARCC Program with successful completion of standard data collection protocol in the Spondylitis Clinic of UHN-Toronto Western Hospital
  • Have sustained inactive disease or LDA with an ASDAS of <2.1 or BASDAI <4 for at least 6 months
  • On a stable dose of a TNFi (infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab)
  • Must not be pregnant

Exclusion Criteria:

  • Adults axSpA patients with active extra-articular manifestations such as inflammatory bowel disease, psoriasis, and/or uveitis
  • Have comorbidities that may preclude clinical assessment (i.e. fibromyalgia or other chronic pain syndromes; chronic inflammatory diseases other than axSpA)
  • Have diagnosed psychiatric or personality disorders
  • Pregnant
  • Not enrolled in the Spondyloarthritis Research Consortium of Canada (SPARCC) Program

Sites / Locations

  • University Health Network - Toronto Western HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tapered doses of TNFi

Standard dose of TNFi

Arm Description

Tapering of TNFi through standardized increases in the dosing interval between drug administration. The tapering dose intervals for each TNFi are designed to decrease the dose from baseline by 75% for 12 weeks, 50% for 24 weeks, and 25% for 12 weeks

Stable doses of TNFi according to the approved summary of product characteristics for biologic agents used in axial spondyloarthritis

Outcomes

Primary Outcome Measures

Proportion of patients able to maintain inactive disease or low disease activity, defined as Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 to 2.1 or Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) of <4 on tapered-dose TNFi
The ASDAS and BASDAI are measures of axial spondyloarthritis disease activity for the past week. The ASDAS has 5 components scored from 0 to 10 (none to very severe). The following formula is used to compute for the ASDAS: (0.121 × back pain score) +(0.058 × score for duration of morning stiffness) + (0.11 × patient global assessment score) + (0.073 × peripheral pain/swelling score) + (0.579 × log(CRP+1)). The scores range from 0 (no disease activity) to infinity (being determined by the level of CRP). The disease is considered inactive if the final score is <1.3, and low if <2.1. The BASDAI consists of six items, with each item being scored from 0 ("none") to 10 ("very severe"). The final BASDAI scores ranges from 0 to 10, with lower scores indicating lower disease activity. A BASDAI of <4 indicates inactive or low disease. As opposed to ASDAS, BASDAI does not include CRP in its formula. Either ASDAS or BASDAI is acceptable in clinical practice.

Secondary Outcome Measures

Proportion of patients experiencing a disease flare by ASDAS or BASDAI
Flare is defined in this study as either of the following: loss of inactive disease or LDA (ASDAS ≥2.1 or BASDAI ≥4) - see definitions above minimal clinically important worsening, defined as an increase in ASDAS by ≥0.9 on two consecutive visits
Proportion of patients with functional limitation measured using the Bath Ankylosing Spondylitis Functional Index (BASFI)
The BASFI measures the degree of functional limitation. It is composed of a set of 10 questions relating to activities during the past week. Each item is scored from 0 ("easy") to 10 ("impossible"). The final BASFI is the mean of the 10 scores with the total score ranging from 0 to 10. Lower scores indicate better physical function.
Mean quality of life in the tapered-dose arm vs. the standard-dose arm measured using the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire
The ASQoL measures health-related quality of life (HRQoL) in subjects with axial spondyloarthritis. The final ASQoL score ranges from 0 to 18, with higher scores indicating worse HRQoL.
Proportion of patients with impaired work productivity and activity measured using the Work Productivity and Activity Impairment Questionnaire for Ankylosing Spondylitis (WPAI:SpA) questionnaire
The WPAI:SpA consists of 6 questions to determine employment status, hours missed from work because of SpA, hours missed from work for other reasons, hours actually worked, the effect of SpA on work productivity while at work, and the effect of SpA on activities outside of work. The 4 scores derived include percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment combining absenteeism and presenteeism, and percentage of impairment in activities performed outside of work. The computed percentage for each sub-scale ranges from 0 to 100. Higher scores indicate greater impairment and less productivity.
Proportion of patients with radiographic progression, defined as an increase in the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) by 2 units
The mSASSS measures the sum of the lumbar and cervical spine score from 0 (no change) to 72 (progression). The score is derived from grading of the anterior aspect of the vertebral bodies of the lumbar spine (T12 to S1) and the cervical spine (C2 to T1). Grading is as follows: 0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), 3 (bridging syndesmophyte), or N (vertebral body not evaluable).
Proportion of patients needing concomitant medication
Concomitant medications will include NSAIDs, conventional synthetic DMARDs, and/or targeted synthetic DMARDs used during the study period
Proportion of patients with any related severe adverse event
Severe adverse event, defined as serious infections requiring systemic antibiotic use and/or hospitalization assessed to be at least possibly related to TNFi use or withdrawal
Factors predicting flare
Factors including but not be limited to the following: sex, human leukocyte antigen (HLA)-B27 status, disease duration, duration of remission, ASDAS at the start of taper, and MRI findings at the time of taper

Full Information

First Posted
October 28, 2021
Last Updated
November 21, 2022
Sponsor
University Health Network, Toronto
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1. Study Identification

Unique Protocol Identification Number
NCT05115903
Brief Title
Biologic Tapering Study of TNF Inhibitors in Axial Spondyloarthritis
Acronym
BIOTAPE
Official Title
A Prospective, Randomized Biologic Tapering Study of TNF Inhibitors in Axial Spondyloarthritis
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 1, 2021 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
March 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Health Network, Toronto

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Current evidence on tapering of tumor necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA) is still hampered by heterogeneity in tapering regimens, selection and performance biases, and lack of data on optimized treatment dosing strategies especially in real-world clinical settings. This study aims to contribute to the ongoing investigation of disease-activity-guided tapering of TNFi in axSpA in the form of a prospective, randomized controlled trial.
Detailed Description
This is a 48-week randomized, controlled, open-label, non-inferiority trial of patients with radiographic or non-radiographic axial spondyloarthritis. The study will include 156 patients with inactive disease or low disease activity (LDA) for at least 6 months on a TNFi at the time of randomization. Participants will be randomized using a 1:1 ratio to either the tapered-dose arm or the standard-dose arm of TNFi. Progressive tapering of TNFi according to a predefined protocol will be allowed as long as the patient is able to maintain inactive disease or LDA during the study period. We hypothesize that, in patients with 6 months or more of inactive or low-activity axial spondyloarthritis, tapered-dose TNFi are non-inferior to standard-dose TNFi in sustaining the disease state for at least 1 year.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Axial Spondyloarthritis
Keywords
spondyloarthritis, TNF inhibitors, tapering

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
156 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Tapered doses of TNFi
Arm Type
Experimental
Arm Description
Tapering of TNFi through standardized increases in the dosing interval between drug administration. The tapering dose intervals for each TNFi are designed to decrease the dose from baseline by 75% for 12 weeks, 50% for 24 weeks, and 25% for 12 weeks
Arm Title
Standard dose of TNFi
Arm Type
Active Comparator
Arm Description
Stable doses of TNFi according to the approved summary of product characteristics for biologic agents used in axial spondyloarthritis
Intervention Type
Drug
Intervention Name(s)
Tapered doses of TNFi
Other Intervention Name(s)
etanercept 50 mg every 10 days (75% of baseline dose), 14 days (50%), 30 days (25%), adalimumab 40 mg every 3 weeks (75%), 4 weeks (50%), 16 weeks (25%), certolizumab pegol 200 mg 3 weeks (75%), 4 weeks (50%), 16 weeks (25%), golimumab 50 mg every 6 weeks (75%), 8 weeks (50%), 16 weeks (25%), infliximab 5 mg/kg every 8 weeks (75%), 12 weeks (50%), 16 weeks (25%)
Intervention Description
To be given subcutaneously via a prefilled syringe/autoinjector (etanercept, adalimumab, certolizumab pegol, golimumab) or intravenously via infusion (infliximab) at increasing dose intervals as specified
Intervention Type
Drug
Intervention Name(s)
Standard dose of TNFi
Other Intervention Name(s)
etanercept 50 mg every 7 days, adalimumab 40 mg every 2 weeks, certolizumab pegol 200 mg every 2 weeks, golimumab 50 mg every 4 weeks, infliximab 5 mg/kg every 6 weeks
Intervention Description
To be given subcutaneously via a prefilled syringe/autoinjector (etanercept, adalimumab, certolizumab pegol, golimumab) or intravenously via infusion (infliximab)
Primary Outcome Measure Information:
Title
Proportion of patients able to maintain inactive disease or low disease activity, defined as Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3 to 2.1 or Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) of <4 on tapered-dose TNFi
Description
The ASDAS and BASDAI are measures of axial spondyloarthritis disease activity for the past week. The ASDAS has 5 components scored from 0 to 10 (none to very severe). The following formula is used to compute for the ASDAS: (0.121 × back pain score) +(0.058 × score for duration of morning stiffness) + (0.11 × patient global assessment score) + (0.073 × peripheral pain/swelling score) + (0.579 × log(CRP+1)). The scores range from 0 (no disease activity) to infinity (being determined by the level of CRP). The disease is considered inactive if the final score is <1.3, and low if <2.1. The BASDAI consists of six items, with each item being scored from 0 ("none") to 10 ("very severe"). The final BASDAI scores ranges from 0 to 10, with lower scores indicating lower disease activity. A BASDAI of <4 indicates inactive or low disease. As opposed to ASDAS, BASDAI does not include CRP in its formula. Either ASDAS or BASDAI is acceptable in clinical practice.
Time Frame
Weeks 12, 24, 36, and 48
Secondary Outcome Measure Information:
Title
Proportion of patients experiencing a disease flare by ASDAS or BASDAI
Description
Flare is defined in this study as either of the following: loss of inactive disease or LDA (ASDAS ≥2.1 or BASDAI ≥4) - see definitions above minimal clinically important worsening, defined as an increase in ASDAS by ≥0.9 on two consecutive visits
Time Frame
Up to Week 48
Title
Proportion of patients with functional limitation measured using the Bath Ankylosing Spondylitis Functional Index (BASFI)
Description
The BASFI measures the degree of functional limitation. It is composed of a set of 10 questions relating to activities during the past week. Each item is scored from 0 ("easy") to 10 ("impossible"). The final BASFI is the mean of the 10 scores with the total score ranging from 0 to 10. Lower scores indicate better physical function.
Time Frame
Up to Week 48
Title
Mean quality of life in the tapered-dose arm vs. the standard-dose arm measured using the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire
Description
The ASQoL measures health-related quality of life (HRQoL) in subjects with axial spondyloarthritis. The final ASQoL score ranges from 0 to 18, with higher scores indicating worse HRQoL.
Time Frame
Up to Week 48
Title
Proportion of patients with impaired work productivity and activity measured using the Work Productivity and Activity Impairment Questionnaire for Ankylosing Spondylitis (WPAI:SpA) questionnaire
Description
The WPAI:SpA consists of 6 questions to determine employment status, hours missed from work because of SpA, hours missed from work for other reasons, hours actually worked, the effect of SpA on work productivity while at work, and the effect of SpA on activities outside of work. The 4 scores derived include percentage of absenteeism, percentage of presenteeism (reduced productivity while at work), an overall work impairment combining absenteeism and presenteeism, and percentage of impairment in activities performed outside of work. The computed percentage for each sub-scale ranges from 0 to 100. Higher scores indicate greater impairment and less productivity.
Time Frame
Up to Week 48
Title
Proportion of patients with radiographic progression, defined as an increase in the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) by 2 units
Description
The mSASSS measures the sum of the lumbar and cervical spine score from 0 (no change) to 72 (progression). The score is derived from grading of the anterior aspect of the vertebral bodies of the lumbar spine (T12 to S1) and the cervical spine (C2 to T1). Grading is as follows: 0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), 3 (bridging syndesmophyte), or N (vertebral body not evaluable).
Time Frame
Baseline and Week 48
Title
Proportion of patients needing concomitant medication
Description
Concomitant medications will include NSAIDs, conventional synthetic DMARDs, and/or targeted synthetic DMARDs used during the study period
Time Frame
Up to Week 48
Title
Proportion of patients with any related severe adverse event
Description
Severe adverse event, defined as serious infections requiring systemic antibiotic use and/or hospitalization assessed to be at least possibly related to TNFi use or withdrawal
Time Frame
Up to Week 48
Title
Factors predicting flare
Description
Factors including but not be limited to the following: sex, human leukocyte antigen (HLA)-B27 status, disease duration, duration of remission, ASDAS at the start of taper, and MRI findings at the time of taper
Time Frame
Up to Week 48

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult axSpA patients satisfying the 2009 Assessment of SpondyloArthritis International Society (ASAS) Classification Criteria Currently enrolled in the SPARCC Program with successful completion of standard data collection protocol in the Spondylitis Clinic of UHN-Toronto Western Hospital Have sustained inactive disease or LDA with an ASDAS of <2.1 or BASDAI <4 for at least 6 months On a stable dose of a TNFi (infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab) Must not be pregnant Exclusion Criteria: Adults axSpA patients with active extra-articular manifestations such as inflammatory bowel disease, psoriasis, and/or uveitis Have comorbidities that may preclude clinical assessment (i.e. fibromyalgia or other chronic pain syndromes; chronic inflammatory diseases other than axSpA) Have diagnosed psychiatric or personality disorders Pregnant Not enrolled in the Spondyloarthritis Research Consortium of Canada (SPARCC) Program
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Patricia Remalante-Rayco, MD
Phone
416-603-5869
Email
patricia.remalante-rayco@uhnresearch.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Robert D. Inman, MD
Phone
416-603-5869
Email
Robert.Inman@uhn.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Robert D. Inman, MD
Organizational Affiliation
University Health Network - Toronto Western Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Health Network - Toronto Western Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5T 2S8
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Patricia Remalante-Rayco, MD
Phone
416-603-5777

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
11955536
Citation
Braun J, Brandt J, Listing J, Zink A, Alten R, Golder W, Gromnica-Ihle E, Kellner H, Krause A, Schneider M, Sorensen H, Zeidler H, Thriene W, Sieper J. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet. 2002 Apr 6;359(9313):1187-93. doi: 10.1016/s0140-6736(02)08215-6.
Results Reference
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PubMed Identifier
16802350
Citation
van der Heijde D, Kivitz A, Schiff MH, Sieper J, Dijkmans BA, Braun J, Dougados M, Reveille JD, Wong RL, Kupper H, Davis JC Jr; ATLAS Study Group. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006 Jul;54(7):2136-46. doi: 10.1002/art.21913.
Results Reference
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PubMed Identifier
18975305
Citation
Inman RD, Davis JC Jr, Heijde Dv, Diekman L, Sieper J, Kim SI, Mack M, Han J, Visvanathan S, Xu Z, Hsu B, Beutler A, Braun J. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 2008 Nov;58(11):3402-12. doi: 10.1002/art.23969.
Results Reference
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PubMed Identifier
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Citation
Navarro-Compan V, Plasencia-Rodriguez C, de Miguel E, Balsa A, Martin-Mola E, Seoane-Mato D, Canete JD. Anti-TNF discontinuation and tapering strategies in patients with axial spondyloarthritis: a systematic literature review. Rheumatology (Oxford). 2016 Jul;55(7):1188-94. doi: 10.1093/rheumatology/kew033. Epub 2016 Mar 21.
Results Reference
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PubMed Identifier
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Gratacos J, Pontes C, Juanola X, Sanz J, Torres F, Avendano C, Vallano A, Calvo G, de Miguel E, Sanmarti R; REDES-TNF investigators. Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis. Arthritis Res Ther. 2019 Jan 8;21(1):11. doi: 10.1186/s13075-018-1772-z.
Results Reference
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Citation
Zhang T, Zhu J, He D, Chen X, Wang H, Zhang Y, Xue Q, Liu W, Xiang G, Li Y, Yu Z, Wu H. Disease activity guided stepwise tapering or discontinuation of rhTNFR:Fc, an etanercept biosimilar, in patients with ankylosing spondylitis: a prospective, randomized, open-label, multicentric study. Ther Adv Musculoskelet Dis. 2020 Jun 2;12:1759720X20929441. doi: 10.1177/1759720X20929441. eCollection 2020.
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Lawson DO, Eraso M, Mbuagbaw L, Joanes M, Aves T, Leenus A, Omar A, Inman RD. Tumor Necrosis Factor Inhibitor Dose Reduction for Axial Spondyloarthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Arthritis Care Res (Hoboken). 2021 Jun;73(6):861-872. doi: 10.1002/acr.24184.
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Biologic Tapering Study of TNF Inhibitors in Axial Spondyloarthritis

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