Interleukin-6 Inhibitors and Drug-drug Interactions in Patients With Rheumatoid Arthritis

NCT ID: NCT04842981

Last Updated: 2023-01-25

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-25
• Study Completion Date: 2022-09-30

Brief Summary

With this study the investigators aim to assess if drug metabolism changes in patients with rheumatoid arthritis when an interleukin (IL)-6 inhibitor is initiated.

Patients with rheumatoid arthritis have an increased level of inflammation in the body which can lead to decreased expression and activity of drug metabolizing enzymes in the liver. This will lead to a decreased metabolism and excretion of drugs. The inflammation is driven by a number of proinflammatory cytokines e.g., IL-6. The investigators hypothesize that patients with rheumatoid arthritis initiating treatment with an IL-6-receptor inhibitor (anti-IL-6R) will obtain a normalization of the activated IL-6-pathway resulting in increased expression and activity of drug metabolizing enzymes and hence increased metabolism. Ultimately, this normalization of drug metabolism could lead to insufficient efficacy of a wide variety of drugs.

The investigators will perform a clinical pharmacokinetic trial. The study will include patients with active rheumatoid arthritis and a need to initiate treatment with an IL-6 receptor antibody. Patients will ingest a 6-drug cocktail consisting of probes for specific CYP enzymes. Plasma and urine will be drawn over 6 hours to determine concentrations of the drugs and their metabolites. Patients will then initiate IL-6 receptor antibody treatment and to assess both short- and long-term impact of altered inflammation, the same 6-drug cocktail will be ingested, and concentrations measured, after three weeks and three months. To help understand the mechanism and the putative involvement of inflammation, markers of inflammation such as cytokines, transcription factors, etc. will also be assesses.

Conditions

Arthritis, Rheumatoid; Interaction

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Interleukin 6 receptor antibody

Tocilizumab, 162 mg subcutaneous, once every week OR Sarilumab, 200 mg subcutaneous, once every two weeks.

Group Type: EXPERIMENTAL

Tocilizumab

Intervention Type: DRUG

Tocilizumab and Sarilumab are considered equal. Patients are assigned the treatment based on national and local guidelines. Intervention will be administered according to the approved posology.

Sarilumab

Intervention Type: DRUG

Tocilizumab and Sarilumab are considered equal. Patients are assigned the treatment based on national and local guidelines. Intervention will be administered according to the approved posology.

Interventions

Tocilizumab

Tocilizumab and Sarilumab are considered equal. Patients are assigned the treatment based on national and local guidelines. Intervention will be administered according to the approved posology.

Intervention Type: DRUG

Sarilumab

Tocilizumab and Sarilumab are considered equal. Patients are assigned the treatment based on national and local guidelines. Intervention will be administered according to the approved posology.

Intervention Type: DRUG

Other Intervention Names

RoActemra; Kevzara

Eligibility Criteria

Inclusion Criteria

• Active rheumatoid arthritis
• Age 18-75 years
• eGFR > 30 mL/min
• absolute neutrophil count (ANC) ≥ 2 x 109 /L
• Platelet count > 150 x 103 /μL (corresponding to >150 x 109 /L)
• ALAT in the normal range or within 1.5x the upper limit of normal.
• Use of effective contraception (only woman of childbearing potential)
• Negative test for hepatitis and tuberculosis

Exclusion Criteria

• Known sensitivity to any of the medications used.
• Active severe infections
• Malignancy
• Diverticulitis
• Intake of medications which can influence the safety of the patient or the results of the study. Can include prescription medications, over-the-counter medications, herbal medicines or dietary supplements. Will be assessed by the investigators.
• Participation in other clinical intervention trials.
• Pregnancy or breastfeeding

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Odense University Hospital

OTHER

Sponsor Role: collaborator

Esbjerg Hospital - University Hospital of Southern Denmark

OTHER

Sponsor Role: collaborator

King Christian X´Hospital for Rheumatic Diseases

OTHER

Sponsor Role: collaborator

Sygehus Lillebaelt

OTHER

Sponsor Role: collaborator

Odense Patient Data Explorative Network

OTHER

Sponsor Role: collaborator

University of Southern Denmark

OTHER

Sponsor Role: lead

Responsible Party

Ann-Cathrine Dunvald

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ann-Cathrine Dunvald, MD

Role: PRINCIPAL_INVESTIGATOR

University of Southern Denmark

Locations

Hospital South West Jutland

Esbjerg, Region Syddanmark, Denmark

Odense University Hospital

Odense, Region Syddanmark, Denmark

Danish Hospital for Rheumatic Diseases

Sønderborg, Region Syddanmark, Denmark

Countries

Denmark

References

Dunvald AD, Soltoft K, Sheetal E, Just SA, Frederiksen IEB, Nielsen F, Olsen DA, Madsen JS, Hendricks O, Stage TB. Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy. Eur J Clin Pharmacol. 2023 Dec;79(12):1687-1698. doi: 10.1007/s00228-023-03578-1. Epub 2023 Oct 13.

Reference Type: DERIVED

PMID: 37831074 (View on PubMed)

Other Identifiers

AKF-398

Identifier Type: -

Identifier Source: org_study_id