Early Adalimumab Induction for Immune Checkpoint Inhibitor Associated Inflammatory Arthritis

• ClinicalTrials.gov Identifier: NCT06037811
• Recruitment Status: Not yet recruiting
• First Posted: September 14, 2023
• Last Update Posted: March 13, 2024
• Sponsor: Tom Appleton
• Collaborators: Canadian Research Group in Immuno-Oncology; Western University
• Information provided by (Responsible Party): Tom Appleton, Lawson Health Research Institute

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Inflammatory Arthritis; Immune-related Adverse Event	Drug: Adalimumab; Drug: Prednisone	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Early Adalimumab Induction for Treatment of Steroid Dependent Immune Checkpoint Inhibitor Associated Inflammatory Arthritis: A Pragmatic Randomized Clinical Trial
• Estimated Study Start Date: April 2024
• Estimated Primary Completion Date: November 2025
• Estimated Study Completion Date: November 2025

Arms and Interventions

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: 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.; Drug: Prednisone; Prednisone as per standard of care.

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. percentage of participants on prednisone [ Time Frame: 24 weeks ]
   Definition of success: Thirty percent difference between the two groups
2. Cumulative prednisone dose [ Time Frame: 24 weeks ]
   Definition of success: Thirty percent difference between the two groups
3. percentage of dose reduction of prednisone [ Time Frame: At 12 and 24 weeks ]
   Definition of success: Thirty percent difference between the two groups
4. percentage of participants with immune-related inflammatory arthritis in remission (based on opinion of investigator) [ Time Frame: at 12 and 24 weeks ]
   Definition of success: Thirty percent difference between the two groups
5. percentage of participants with immune-related inflammatory arthritis resolution (based on opinion of investigator) [ Time Frame: at 12 and 24 weeks ]
   Definition of success: Thirty percent difference between the two groups

Other Outcome Measures:

1. percentage of participants with persistent active synovitis/tenosynovitis (yes/no) [ Time Frame: at 12 and 24 weeks ]
   Differences between treatment groups ≥20% will be considered significant
2. percentage of participants treated with methotrexate and/or hydroxychloroquine [ Time Frame: at 12 and 24 weeks ]
   Differences between treatment groups ≥20% will be considered significant
3. MDGA (MD global assessment) of arthritis 0 to 10 [ Time Frame: at weeks 12 and 24 ]
   Differences between treatment groups ≥20% will be considered significant
4. Participant reported pain on a visual analog scale from 0 to 10. [ Time Frame: at weeks 12 and 24 ]
   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.
5. PGA (patient global assessment) of arthritis 0-10 [ Time Frame: at weeks 12 and 24 ]
   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.
6. FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue Score) [ Time Frame: at weeks 12 and 24 ]
   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.
7. EQ-5D (EuroQol 5 Dimension for evaluation of generic quality of life) [ Time Frame: at weeks 12 and 24 ]
   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.
8. Cancer status vs baseline: overall survival (OS), progression free survival (PFS) [ Time Frame: at 12 and 24 weeks ]
   Differences between treatment groups ≥20% will be considered significant
9. Number of participants who continue, hold or stop ICI therapy [ Time Frame: at 12 and 24 weeks ]
   Differences between treatment groups ≥20% will be considered significant
10. Feasibility: Number of participating sites; Number of participants screened, consented, randomized, and followed-up at each participating site [ Time Frame: at week 24 ]
    Differences between treatment groups ≥20% will be considered significant
11. The rates of AEs, serious AEs (according to CTCAE), and clinical laboratory abnormalities [ Time Frame: at 12 and 24 weeks ]
    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%)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Tom Appleton, MD, PhD, FRCPC; 519-646-6100; tom.appelton@sjhc.london.on.ca

Sponsors and Collaborators

Tom Appleton

Canadian Research Group in Immuno-Oncology

Western University

More Information

• Responsible Party: Tom Appleton, Principal Investigator, Lawson Health Research Institute
• ClinicalTrials.gov Identifier: NCT06037811
• Other Study ID Numbers: CanRIO ADA2023
• First Posted: September 14, 2023
• Last Update Posted: March 13, 2024
• Last Verified: March 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Keywords provided by Tom Appleton, Lawson Health Research Institute:

Immune Checkpoint Inhibitor; Adalimumab; TNF-alpha inhibitor

Additional relevant MeSH terms:

Arthritis; Joint Diseases; Musculoskeletal Diseases; Prednisone; Adalimumab; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Tumor Necrosis Factor Inhibitors; Antirheumatic Agents