Clinical trial NCT06440629: Effect of Proactive Therapeutic Drug Monitoring on Maintenance of Sustained Disease Control in Adults With Rheumatoid Arthritis on a Subcutaneous TNF Inhibitor: The Rheumatoid Arthritis Therapeutic DRUg Monitoring Trial (RA-DRUM)
Official title: A Multi-center, Open, Randomized, 18-month, Parallel-group, Superiority Study to Compare the Effect of Proactive Therapeutic Drug Monitoring Versus Standard of Care With Regards to Maintenance of Sustained Disease Control Without Flare in Adults With Rheumatoid Arthritis Treated With a Subcutaneous Tumor Necrosis Factor Inhibitor
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid arthritis
Therapeutic drug monitoring
Tumor necrosis factor inhibitor
Lead sponsor: Diakonhjemmet Hospital
Sponsor class: OTHER
Collaborators: name: Oslo University Hospital
name: Karolinska University Hospital
name: Queen Mary University of London
name: Medical University of Vienna
name: Alesund Hospital
name: St. Olavs Hospital
name: Helse Stavanger HF
name: Drammen sykehus
name: University Hospital of North Norway
name: Førde Hospital Trust
name: Hospital of Southern Norway Trust
name: Haukeland University Hospital
name: Ostfold Hospital Trust
name: Lillehammer Hospital for Rheumatic Diseases
name: Martina Hansen's Hospital
name: Haugesund Rheumatism Hospital
name: Betanien Hospital
name: Helgeland Hospital Trust
name: Nordlandssykehuset HF
name: Carol Davila University of Medicine and Pharmacy
First posted: 2024-06-04
Enrollment: 350
Sex: ALL
Minimum age (years): 18
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to compare therapeutic drug monitoring (TDM) versus Standard of care in patients with rheumatoid arthritis treated with a subcutaneous tumor necrosis factor inhibitor (adalimumab).

The main question it aims to answer is:

Is TDM superior to standard of care in order to maintain sustained disease control without flares?

Participants will be followed with blood sampling every second month, measuring serum drug levels and anti-drug antibodies of the TNFi. In the TDM-group, the researchers will adjust the dosage of the TNFi based on knowledge on optimal therapeutic ranges. In the Standard of care group, the TNFi will be administered according to standard of care without knowledge of serum drug levels or anti-drug antibodies.

Detailed description: There is a considerable variation in serum drug levels among rheumatoid arthritis (RA) patients on tumor necrosis factor inhibitors (TNFi), and a high number develop neutralizing anti-drug antibodies (ADAb). Sub-therapeutic drug levels and ADAb formation are major contributors to TNFi treatment failure and disease flare. Proactive therapeutic drug monitoring (TDM), i.e., individualized drug dosing based on regular assessments of serum drug levels and ADAb, has the potential to optimize the efficacy and safety of TNFi treatment.

The aim of the RA-DRUM trial is to assess whether TDM is superior to standard of care in order to maintain sustained disease control without flares in patients with RA treated with the SC TNFi adalimumab.

Participants will be randomized to:

* Administration of TNFi based on proactive TDM (TDM group)
* Administration of TNFi based on standard of care without knowledge of serum drug levels or ADAb status (Standard of care group)

Participants will be followed for 18 months with on-site visits at baseline, 4, 8, 12 and 18 months and digital visits at 2, 6, 10, 14, and 16 months. Blood sampling for serum drug levels and anti-drug antibodies will be done at all visits.

Eligibility criteria: Inclusion Criteria:

1. A clinical diagnosis of RA
2. ≥ 18 and under 75 years of age at screening
3. On stable therapy with standard dose of a SC TNFi (adalimumab) for a minimum of 3 months and a maximum of 24 months
4. In low disease activity or remission (DAS28-CRP under 3.2) and indication for continuation of treatment according to the treating physician
5. Subject capable of understanding and signing an informed consent form

Exclusion Criteria:

1. Major comorbidities, such as previous malignancies within the last 5 years, uncontrolled diabetes mellitus, severe infections (including HIV), uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4), severe respiratory diseases, demyelinating disease, significant chronic widespread pain syndrome, significant renal or hepatic disease, and/or other diseases or conditions which either contraindicate treatment with SC TNFi or make adherence to the protocol difficult
2. Hypersensitivity to sc TNFi (adalimumab).
3. Pregnancy, or subject considering becoming pregnant during the study period
4. Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers, or other factors that makes adherence to the study protocol difficult
5. Changes in csDMARD co-medication, including dose changes of csDMARD or changes in the dose of corticosteroids within the last 2 months
6. Co-medication with bDMARD, tsDMARD, or other immunosuppressive drugs (excluding csDMARD and corticosteroids ≤ 7.5 mg prednisolone (or equivalent) once daily).
7. Active participation in any other interventional study.
8. In need of live vaccines during the study period.

Primary outcomes:
measure: Sustained disease control over the follow-up period of 18 months without flare
timeFrame: 4, 8, 12, 18 months
Secondary outcomes:
measure: Disease activity assessed by Disease Activity Score using 28 joints C-reactive protein (DAS28-CRP)
timeFrame: 4, 8, 12, and 18 months
measure: Disease activity measured by 44 joint count
timeFrame: 4, 8, 12, and 18 months
measure: Patient Global assessment of disease activity (PGA)
timeFrame: 4, 8, 12, and 18 months
measure: Evaluators Global Assessment of Disease Activity (EGA)
timeFrame: 4, 8, 12, and 18 months
measure: Disease activity assessed by Clinical Disease Activity Index (CDAI)
timeFrame: 4, 8, 12, and 18 months
measure: Disease activity assessed by Simple Disease Activity Index (SDAI)
timeFrame: 4, 8, 12, and 18 months
measure: Remission assessed by American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) remission criteria
timeFrame: 4, 8, 12, and 18 months
measure: Rheumatoid Arthritis Impact of Disease (RAID)
timeFrame: 4, 8, 12, and 18 months
measure: Evaluation of physical function measured by Modified Health Assessment Questionnaire (MHAQ)
timeFrame: 4, 8, 12, and 18 months
measure: Number and type of adverse events (AE)
timeFrame: 4, 8, 12, and 18 months
measure: Drug survival
timeFrame: 4, 8, 12, and 18 months
measure: Drug consumption
timeFrame: 18 months
measure: Occurrence of anti-drug antibodies (ADAb)
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
measure: Serum drug levels
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
Other outcomes:
measure: European Quality of Life 5 Dimensions (EQ-5D)
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
measure: 36-Item Short-form health survey (SF-36)
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
measure: Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis (WPAI:RA)
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
measure: Rheumatoid arthritis flare questionnaire (RA-FQ)
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
measure: Adherence
timeFrame: 2, 4, 6, 8, 10, 12, 14, 16, 18 months
measure: Co-medication
timeFrame: 4, 8, 12, and 18 months
measure: Consentration of C-reactive protein (CRP)
timeFrame: 4, 8, 12, and 18 months
measure: Erythrocyte sedimentation rate (ESR)
timeFrame: 4, 8, 12, and 18 months
Locations:
city: Vienna
country: Austria
facility: Medical University Vienna
city: Oslo
country: Norway
facility: Diakonhjemmet sykehus
state: N-0319
city: Bergen
country: Norway
facility: Haukeland University Hospital
city: Bodø
country: Norway
facility: Nordland Hospital Trust
city: Drammen
country: Norway
facility: Drammen Hospital
city: Førde
country: Norway
facility: Førde Hospital Trust
city: Haugesund
country: Norway
facility: Haugesund Rheumatism Hospital
city: Kristiansand
country: Norway
facility: Hospital of Southern Norway Trust
city: Lillehammer
country: Norway
facility: Lillehammer Hospital for Rheumatic Diseases
city: Mo I Rana
country: Norway
facility: Helgeland Hospital Trust
city: Moss
country: Norway
facility: Østfold Hospital Trust
city: Sandvika
country: Norway
facility: Martina Hansen's Hospital
city: Skien
country: Norway
facility: Betanien Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tromsø
country: Norway
facility: University Hospital of North Norway
city: Trondheim
country: Norway
facility: St.Olavs Hospital
city: Ålesund
country: Norway
facility: Ålesund Hospital
city: Bucharest
country: Romania
facility: Carol Davila University of Medicine and Pharmacy Bucharest
city: Gothenburg
country: Sweden
facility: Sahlgrenska Universitetssjukehuset
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: London
country: United Kingdom
facility: Queen Mary
state: Sw15 5pn
Study officials:
affiliation: Diakonhjemmet Hospital
name: Espen A Haavardsholm, Phd, MD
role: STUDY_DIRECTOR
References: