Clinical trial NCT04842981: Interleukin-6 Inhibitors and Drug-drug Interactions in Patients With Rheumatoid Arthritis
Official title: Interleukin-6 Inhibitors and Drug-drug Interactions in Patients With Rheumatoid Arthritis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Arthritis, Rheumatoid
Interaction
Lead sponsor: University of Southern Denmark
Sponsor class: OTHER
Collaborators: name: Odense University Hospital
name: Esbjerg Hospital - University Hospital of Southern Denmark
name: King Christian X´Hospital for Rheumatic Diseases
name: Sygehus Lillebaelt
name: Odense Patient Data Explorative Network
First posted: 2021-04-13
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.


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

Primary outcomes:
measure: Short-term change in CYP3A4 activity assessed by midazolam metabolic ratio.
timeFrame: 3 weeks
Secondary outcomes:
measure: Long-term change in CYP3A4 activity assessed by midazolam metabolic ratio.
timeFrame: 12 weeks
measure: Short-term change in CYP1A2 activity assessed by caffeine metabolic ratio.
timeFrame: 3 weeks
measure: Long-term change in CYP1A2 activity assessed by caffeine metabolic ratio.
timeFrame: 12 weeks
measure: Short-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.
timeFrame: 3 weeks
measure: Long-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.
timeFrame: 12 weeks
measure: Short-term change in CYP2C9 activity assessed by losartan metabolic ratio.
timeFrame: 3 weeks
measure: Long-term change in CYP2C9 activity assessed by losartan metabolic ratio.
timeFrame: 12 weeks
measure: Short-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.
timeFrame: 3 weeks
measure: Long-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.
timeFrame: 12 weeks
measure: Short-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.
timeFrame: 3 weeks
measure: Long-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.
timeFrame: 12 weeks
Other outcomes:
measure: Change in inflammation assessed by measurement of a panel of cytokines.
timeFrame: 3 weeks and 12 weeks
Locations:
city: Esbjerg
country: Denmark
facility: Hospital South West Jutland
state: Region Of Southern Denmark
city: Odense
country: Denmark
facility: Odense University Hospital
state: Region Of Southern Denmark
city: Sønderborg
country: Denmark
facility: Danish Hospital for Rheumatic Diseases
state: Region Of Southern Denmark
Study officials:
affiliation: University of Southern Denmark
name: Ann-Cathrine Dunvald, MD
role: PRINCIPAL_INVESTIGATOR
References: