Therapeutic Drug Monitoring-baSed adalimuMab De-escalatiOn in nOn-infecTious cHronic Uveitis (SMOOTH)

Therapeutic Drug Monitoring-baSed adalimuMab De-escalatiOn in nOn-infecTious cHronic Uveitis: an Open-label, Non-inferiority, Randomised Clinical Trial

Uveitis and its complications are thought to account for 10 to 15% of preventable blindness in Western countries. The diagnosis of chronic non-infectious uveitis (CNUI) can be made after exclusion of pseudo uveitis or infectious uveitis, in the case of any persistent uveitis or uveitis with frequent relapses occurring less than 3 months after cessation of treatment. Adalimumab (ADA), an anti-TNFα monoclonal antibody, has marketing authorization and is widely used in the treatment of UCNI as a relay to corticosteroids. The use of ADA has been optimized, in particular through Therapeutic Drug Monitoring (TDM), based on the determination of serum ADA levels and anti-ADA antibodies. Recently, an article showed that a strategy of spacing ADA administrations in RA patients with concentrations >8 μg/mL was not inferior to standard.

Study Overview

• Status: Not yet recruiting
• Conditions: Uveitis; Chronic Disease
• Intervention / Treatment: Diagnostic test: Blood sample; Drug: Adalimumab Injection

Detailed Description

There is currently no formal recommendation for spacing ADA administration in patients with chronic noninfectious uveitis, but promising data from a recent retrospective study conducted by the Croix-Rousse team, led to the proposal of a decision support algorithm. Following the example of what has been shown in rheumatoid arthritis, the investigators propose to compare a strategy of spacing ADA administrations in patients with a satisfactory clinical response associated with high serum ADA concentrations.

• Study Type: Interventional
• Enrollment (Estimated): 320
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Lucile GRANGE, MD; Phone Number: +33 (0)477828245; Email: lucile.grange@chu-st-etienne.fr
• Study Contact Backup: Name: Martin KILLIAN, MD; Phone Number: +33 (0)477829179; Email: martin.killian@chu-st-etienne.fr

Study Locations

• France
  • Avignon, France, 84000
    • CH Avignon
  • Clermont-Ferrand, France, 63003
    • Chu Montpied
  • Grenoble, France, 38700
    • Chu Grenoble Alpes
  • Le Puy-en-Velay, France, 43000
    • CH Le Puy-en-Velay
  • Lyon, France, 69317
    • Hôpital de la Croix Rousse
  • Lyon, France
    • HCL - Hôpital Edouard Herriot
  • Montpellier, France, 34090
    • CHU MONTPELLIER - Hôpital Saint-Eloi
  • Paris, France, 75013
    • APHP - Hôpital Pitié-Salpétrière
  • Paris, France, 75014
    • APHP - Hôpital Cochin
  • Paris, France, 75012
    • APHP - Centre hospitalier national des Quinze-Vingts
  • Saint-Étienne, France, 42055
    • CHU de Saint-Etienne
    • Contact: Lucile GRANGE, MD; Phone Number: +33 (0)477828245; Email: lucile.grange@chu-st-etienne.fr
    • Contact: Martin KILLIAN, MD; Phone Number: +33 (0)477829179; Email: martin.killian@chu-st-etienne.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Informed and having signed the study consent form
• Age ≥ 18 years
• NICU according to the Standardization of Uveitis Nomenclature (SUN) criteria
• Complete ophthalmological response for ≥ 48 weeks (96 weeks for uveitis related to Behçet's disease), all treatments combined
• On ADA 40mg / 14 days for ≥ 24 weeks (i.e. achievement of the steady state for ADA concentrations)
• Not having received systemic corticosteroid therapy for ≥ 12 weeks

Exclusion Criteria:

• Inability or refusal to understand and/or sign the informed consent form to participate in the study.
• Inability and/or refusal to carry out the follow-up examinations required for the study.
• Modification of any background immunomodulatory treatment (e.g. methotrexate, hydroxychloroquine, mycophenolate, etc.) associated with ADA, during the 12 weeks prior to inclusion.
• Uveitis suspected or proven to be of infectious origin
• Planned surgery (or other foreseeable medical event) requiring discontinuation of ADA for the duration of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control arm : conventional strategy; At W0, ADA administration will be continued every 14 days. At W24, the control arm will continue to receive ADA every 14 days regardless of serum ADA concentration.	Diagnostic test: Blood sample; A blood sample will be taken, in addition to blood samples taken for the usual follow-up, with 4 dry tubes for the determination of ADA and anti-ADA antibodies and for bio-collection.; Drug: Adalimumab Injection; Adalimumab Injection
Experimental: Arm 2: Interventional arm : adalimumab dose spacing strategy; At W0, if the serum ADA concentration is ≥ 8 μg/mL, ADA administration will be spaced every 21 days. At W24, if the ADA concentration is < 3.3 μg/mL (having a serum ADA concentration above this threshold was associated with a complete therapeutic response according to one study), administrations will be repeated every 14 days. If the ADA concentration is ≥ 3.3 and < 8μg/mL, administrations will be left every 21 days. If ADA concentration is still ≥8μg/mL, ADA administrations will be spaced every 28 days.	Diagnostic test: Blood sample; A blood sample will be taken, in addition to blood samples taken for the usual follow-up, with 4 dry tubes for the determination of ADA and anti-ADA antibodies and for bio-collection.; Drug: Adalimumab Injection; Adalimumab Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintenance of a complete ophthalmological response at 48 weeks	Number of patient with complete ophthalmological response. Ophtalmological response is defined as number of patient with, in both eyes, absence of inflammatory lesions (0 = absence) AND a cellular grade of the anterior chamber and vitreous ≤ 0.5+.	Week 48
Infection	Number of infection during follow-up for up to 48 weeks. Any suspected infectious event will have to be validated by a healthcare professional based on the presence of suggestive clinical signs (purulent sputum, fever ≥38°C, inflammatory syndrome, positive microbiological examination, etc.) via dedicated forms and validated by an adjudication committee.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maintenance of a complete ophthalmological response at 12 weeks	Number of patient with complete ophthalmological response. Ophtalmological response is defined as number of patient with, in both eyes, absence of inflammatory lesions (0 = absence) AND a cellular grade of the anterior chamber and vitreous ≤ 0.5+.	Weeks 12
Maintenance of a complete ophthalmological response at 24 weeks	Number of patient with complete ophthalmological response. Ophtalmological response is defined as number of patient with, in both eyes, absence of inflammatory lesions (0 = absence) AND a cellular grade of the anterior chamber and vitreous ≤ 0.5+.	Weeks 24
Maintenance of a complete ophthalmological response at 36 weeks	Number of patient with complete ophthalmological response. Ophtalmological response is defined as number of patient with, in both eyes, absence of inflammatory lesions (0 = absence) AND a cellular grade of the anterior chamber and vitreous ≤ 0.5+.	Weeks 36
Infection	Number of infection during follow-up for up to 12 weeks. Any suspected infectious event will have to be validated by a healthcare professional based on the presence of suggestive clinical signs (purulent sputum, fever ≥38°C, inflammatory syndrome, positive microbiological examination, etc.) via dedicated forms and validated by an adjudication committee.	Week 12
Infection	Number of infection during follow-up for up to 24 weeks. Any suspected infectious event will have to be validated by a healthcare professional based on the presence of suggestive clinical signs (purulent sputum, fever ≥38°C, inflammatory syndrome, positive microbiological examination, etc.) via dedicated forms and validated by an adjudication committee.	Week 24
Infection	Number of infection during follow-up for up to 36 weeks. Any suspected infectious event will have to be validated by a healthcare professional based on the presence of suggestive clinical signs (purulent sputum, fever ≥38°C, inflammatory syndrome, positive microbiological examination, etc.) via dedicated forms and validated by an adjudication committee.	Week 36
Anti-ADA antibody positivity	Anti-ADA antibody positivity by a "drug sensible" test (i-Tracker anti-ADA) in μg/mL	Weeks 12
Anti-ADA antibody positivity	Anti-ADA antibody positivity by a "drug sensible" test (i-Tracker anti-ADA) in μg/mL	Weeks 24
Anti-ADA antibody positivity	Anti-ADA antibody positivity by a "drug sensible" test (i-Tracker anti-ADA) in μg/mL	Weeks 36
Anti-ADA antibody positivity	Anti-ADA antibody positivity by a "drug sensible" test (i-Tracker anti-ADA) in μg/mL	Weeks 48

Collaborators and Investigators

• Sponsor: Centre Hospitalier Universitaire de Saint Etienne
• Collaborators: Direction Générale de l'Offre de Soins
• Investigators: Principal Investigator: Lucile GRANGE, MD, CHU SAINT-ETIENNE

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2025
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2029

Study Registration Dates

• First Submitted: April 25, 2024
• First Submitted That Met QC Criteria: April 29, 2024
• First Posted (Actual): April 30, 2024

Study Record Updates

• Last Update Posted (Actual): May 7, 2024
• Last Update Submitted That Met QC Criteria: May 6, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Therapeutic drug monitoring; Uveitis; Adalimumab
• Additional Relevant MeSH Terms: Pathologic Processes; Eye Diseases; Disease Attributes; Uveal Diseases; Chronic Disease; Uveitis; Anti-Inflammatory Agents; Antirheumatic Agents; Tumor Necrosis Factor Inhibitors; Adalimumab
• Other Study ID Numbers: 23PH187; 2023-509733-39-00 (Other Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No