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

NCT04842981 | Terminated Phase 1

• 1 other identifier: AKF-398
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 3

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

Outcome Measures

Primary Outcomes (1)

• Short-term change in CYP3A4 activity assessed by midazolam metabolic ratio.

  A change in metabolic ratio of midazolam after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of midazolam is used to assess the activity of CYP3A4.

  3 weeks

Secondary Outcomes (11)

• Long-term change in CYP3A4 activity assessed by midazolam metabolic ratio.

  12 weeks

• Short-term change in CYP1A2 activity assessed by caffeine metabolic ratio.

  3 weeks

• Long-term change in CYP1A2 activity assessed by caffeine metabolic ratio.

  12 weeks

• Short-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.

  3 weeks

• Long-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.

  12 weeks

Other Outcomes (1)

• Change in inflammation assessed by measurement of a panel of cytokines.

  3 weeks and 12 weeks

Study Arms (1)

Interleukin 6 receptor antibody

EXPERIMENTAL

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

Drug: Tocilizumab; Drug: Sarilumab

Interventions

Tocilizumab 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.

Also known as: RoActemra

Interleukin 6 receptor antibody

Sarilumab 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.

Also known as: Kevzara

Interleukin 6 receptor antibody

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Southern Denmark: lead
• Odense University Hospital: collaborator
• Esbjerg Hospital - University Hospital of Southern Denmark: collaborator
• King Christian X´Hospital for Rheumatic Diseases: collaborator
• Sygehus Lillebaelt: collaborator
• Odense Patient Data Explorative Network: collaborator

Study Sites (3)

Hospital South West Jutland

Esbjerg, Region Syddanmark, 6700, Denmark

Location

Odense University Hospital

Odense, Region Syddanmark, 5000, Denmark

Location

Danish Hospital for Rheumatic Diseases

Sønderborg, Region Syddanmark, 6400, Denmark

Location

Related Publications (1)

• 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.

  PMID: 37831074 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

tocilizumab; sarilumab

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Ann-Cathrine Dunvald, MD

  University of Southern Denmark

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: March 23, 2021
• First Posted: April 13, 2021
• Study Start: May 25, 2021
• Primary Completion: September 30, 2022
• Study Completion: September 30, 2022
• Last Updated: January 25, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

DK (3)