Early Adalimumab Induction for Immune Checkpoint Inhibitor Associated Inflammatory Arthritis

Early Adalimumab Induction for Treatment of Steroid Dependent Immune Checkpoint Inhibitor Associated Inflammatory Arthritis: A Pragmatic Randomized Clinical Trial

This study will examine the effectiveness of administering adalimumab as a treatment for patients in the early stages of steroid-dependent immune checkpoint Inhibitor associated inflammatory arthritis (ir-IA). Adalimumab (ADA) is a TNF inhibitor (TNFi) that is well established as a standard of care treatment for numerous types of inflammatory arthritis. It is hoped that adalimumab at the early stages of the ir-IA will reduce the symptoms and therefore reduce the need for steroids. This study is a pragmatic randomized clinical trial. Patients will be randomized 1:1 to each treatment group. To evaluate the steroid sparing effect of early induction six doses of Adalimumab will be administered to patients in the study treatment arm as compared to the usual standard of care of a predefined corticosteroid regimen and taper at 12 weeks administered in the control group.

Study Overview

• Status: Not yet recruiting
• Conditions: Inflammatory Arthritis; Immune-related Adverse Event
• Intervention / Treatment: Drug: Prednisone; Drug: Adalimumab

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Tom Appleton, MD, PhD, FRCPC; Phone Number: 519-646-6100; Email: tom.appelton@sjhc.london.on.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Patients are deemed eligible for study participation if they meet all the following:

  • Adult patients (age 18 or older)
  • New (within the last 6 months prior to enrollment) inflammatory arthritis defined by any of the following at the time of screening (either on physical exam or by ultrasound) by a certified rheumatologist:
• 1 or more swollen joints OR
• 1 or more tenosynovitis OR

• 1 or more enthesitis

  • Arthritis onset with taking ICI therapy OR within 4 weeks of stopping ICI therapy including CTLA-4, PD-1, and PDL-1 inhibitors
  • Initiation of ICI therapy must predate the onset of inflammatory arthritis
  • Arthritis either does not respond completely to prednisone doses of 10mg (equivalent) OR recurs with prednisone taper below 10mg daily.
  • Negative tuberculosis (TB) status within the past 12 months (TB skin test or quantiferon) for the patients in the adalimumab group. If not available, the status should be confirmed within 6 months of enrollment in the study (adalimumab group only)
  • Written informed consent provided by patient or power of attorney

Exclusion Criteria:

• Patients are excluded if they meet any of the following:

• Previous diagnosis of inflammatory arthritis or other rheumatic disease (prior to current acute episode)

  • Including but not limited to: rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren's syndrome, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, systemic vasculitis, undifferentiated inflammatory arthritis, undifferentiated connective tissue disease
• Tenosynovitis, synovitis or enthesitis attributed to another cause, fracture or acute gout/CPPD flare.

• Presence of a contraindication to adalimumab therapy

  • Any of the following in the 7 days prior to initiation of adalimumab: positive tuberculin skin test (>5mm induration within 48 to 72 hours) or positive quantiferon, evidence of untreated active infection including fungal infection, opportunistic infection, hepatitis B/C, or HIV
  • Personal history of congestive heart failure
  • Personal or family history of demyelinating neurologic disease
• History of previous TNF inhibitor use
• Current use of other disease modifying agents including: Chloroquine, Sulfasalazine, Azathioprine, 6-MP, and Leflunomide
• Presence of a concomitant non-rheumatic irAE which required systemic immunosuppression within the past 3 months e.g. pneumonitis, hepatitis, colitis, scleritis, nephritis
• Require chronic steroid treatment for adrenal insufficiency or another medical reason other than ir-IA
• Pregnancy, breastfeeding or childbearing potential without practicing highly effective contraception.
• Inability to participate in follow-up visits

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care group; Prednisone 10 mg daily for 2 weeks, then taper by 2.5 mg every 2 weeks until stopped.	Drug: Prednisone; Prednisone as per standard of care.
Active Comparator: Adalimumab group; Adalimumab 40 mg subcutaneous every 2 weeks for 6 doses (12 weeks) + Prednisone 10 mg daily for 2 weeks, tapering by 2.5 mg every 2 weeks until stopped.	Drug: Prednisone; Prednisone as per standard of care.; Drug: Adalimumab; Participants will be randomized 1:1 (non-blinded) to receive either adalimumab (40 mg subcutaneous every 2 weeks for 12 weeks) and prednisone vs prednisone alone. Addition of methotrexate (MTX) and/or hydroxychloroquine (HCQ) is permitted, as needed, at the discretion of the treating rheumatologist. No additional conventional synthetic, targeted synthetic or biologic DMARDs are permitted during the trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of participants on prednisone	Definition of success: Thirty percent fewer participants on prednisone in Group 2 vs Group 1.	at 12 weeks
Cumulative prednisone dose	Definition of success: Thirty percent reduction in the cumulative dose of steroids in Group 2 compared to Group 1.	at 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of participants on prednisone	Definition of success: Thirty percent difference between the two groups	24 weeks
Cumulative prednisone dose	Definition of success: Thirty percent difference between the two groups	24 weeks
percentage of dose reduction of prednisone	Definition of success: Thirty percent difference between the two groups	At 12 and 24 weeks
percentage of participants with immune-related inflammatory arthritis in remission (based on opinion of investigator)	Definition of success: Thirty percent difference between the two groups	at 12 and 24 weeks
percentage of participants with immune-related inflammatory arthritis resolution (based on opinion of investigator)	Definition of success: Thirty percent difference between the two groups	at 12 and 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
percentage of participants with persistent active synovitis/tenosynovitis (yes/no)	Differences between treatment groups ≥20% will be considered significant	at 12 and 24 weeks
percentage of participants treated with methotrexate and/or hydroxychloroquine	Differences between treatment groups ≥20% will be considered significant	at 12 and 24 weeks
MDGA (MD global assessment) of arthritis 0 to 10	Differences between treatment groups ≥20% will be considered significant	at weeks 12 and 24
Participant reported pain on a visual analog scale from 0 to 10.	Enhancement of quality of life due to ADA will be defined as 50% improvement in any of these readouts in ≥50% of participants at weeks 12 and 24 compared to Group 1.	at weeks 12 and 24
PGA (patient global assessment) of arthritis 0-10	Enhancement of quality of life due to ADA will be defined as 50% improvement in any of these readouts in ≥50% of participants at weeks 12 and 24 compared to Group 1.	at weeks 12 and 24
FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue Score)	Enhancement of quality of life due to ADA will be defined as 50% improvement in any of these readouts in ≥50% of participants at weeks 12 and 24 compared to Group 1.	at weeks 12 and 24
EQ-5D (EuroQol 5 Dimension for evaluation of generic quality of life)	Enhancement of quality of life due to ADA will be defined as 50% improvement in any of these readouts in ≥50% of participants at weeks 12 and 24 compared to Group 1.	at weeks 12 and 24
Cancer status vs baseline: overall survival (OS), progression free survival (PFS)	Differences between treatment groups ≥20% will be considered significant	at 12 and 24 weeks
Number of participants who continue, hold or stop ICI therapy	Differences between treatment groups ≥20% will be considered significant	at 12 and 24 weeks
Feasibility: Number of participating sites; Number of participants screened, consented, randomized, and followed-up at each participating site	Differences between treatment groups ≥20% will be considered significant	at week 24
The rates of AEs, serious AEs (according to CTCAE), and clinical laboratory abnormalities	ADA will be considered 'safe' if the frequency of moderate AEs in Group 2 does not exceed 50% (reported rate of moderate AE in RA is 41%)	at 12 and 24 weeks

Collaborators and Investigators

• Sponsor: Tom Appleton
• Collaborators: Western University; Canadian Research Group in Immuno-Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: August 31, 2023
• First Submitted That Met QC Criteria: September 7, 2023
• First Posted (Actual): September 14, 2023

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Adalimumab; Immune Checkpoint Inhibitor; TNF-alpha inhibitor
• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Arthritis; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Tumor Necrosis Factor Inhibitors; Adalimumab; Prednisone
• Other Study ID Numbers: CanRIO ADA2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• 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