Arthritis, RheumatoidPhase 1/2NCT04842981
Interleukin-6 Inhibitors and Drug-drug Interactions in Patients With Rheumatoid Arthritis
A Phase 1/2 study testing Tocilizumab and Sarilumab in people with Arthritis, Rheumatoid and Interaction, run by University of Southern Denmark at 3 sites in Denmark.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Arthritis, Rheumatoid, Interaction
- What is being tested?
- Tocilizumab and Sarilumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 3 sitesDenmark
- Study dates
- 25 May 2021to 30 Sep 2022
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
3 sites in 1 country.
Denmark3 sites
Hospital South West Jutland
Esbjerg, Region Syddanmark, 6700
Odense University Hospital
Odense, Region Syddanmark, 5000
Danish Hospital for Rheumatic Diseases
Sønderborg, Region Syddanmark, 6400
About this study
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
- Being tested
- Tocilizumab, Sarilumab
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TocilizumabDrug
Also called RoActemra
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.
SarilumabDrug
Also called Kevzara
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.
| Study group | Role | What they receive |
|---|---|---|
| Interleukin 6 receptor antibody | Experimental | Tocilizumab, 162 mg subcutaneous, once every week OR Sarilumab, 200 mg subcutaneous, once every two weeks. Receives: Drug: Tocilizumab; Drug: Sarilumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 3 weeks
Secondary outcomes (11)
Long-term change in CYP3A4 activity assessed by midazolam metabolic ratio.
A change in metabolic ratio of midazolam after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of midazolam is used to assess the activity of CYP3A4.
Measured: 12 weeks
Short-term change in CYP1A2 activity assessed by caffeine metabolic ratio.
A change in metabolic ratio of caffeine after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of caffeine is used to assess the activity of CYP1A2.
Measured: 3 weeks
Long-term change in CYP1A2 activity assessed by caffeine metabolic ratio.
A change in metabolic ratio of caffeine after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of caffeine is used to assess the activity of CYP1A2.
Measured: 12 weeks
Short-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.
A change in metabolic ratio of efavirenz after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of efavirenz is used to assess the activity of CYP2B6.
Measured: 3 weeks
Long-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.
A change in metabolic ratio of efavirenz after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of efavirenz is used to assess the activity of CYP2B6.
Measured: 12 weeks
Short-term change in CYP2C9 activity assessed by losartan metabolic ratio.
A change in metabolic ratio of losartan after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of losartan is used to assess the activity of CYP2C9.
Measured: 3 weeks
Long-term change in CYP2C9 activity assessed by losartan metabolic ratio.
A change in metabolic ratio of losartan after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of losartan is used to assess the activity of CYP2C9.
Measured: 12 weeks
Short-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.
A change in metabolic ratio of omeprazole after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of omeprazole is used to assess the activity of CYP2C9.
Measured: 3 weeks
Long-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.
A change in metabolic ratio of omeprazole after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of omeprazole is used to assess the activity of CYP2C9.
Measured: 12 weeks
Short-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.
A change in metabolic ratio of metoprolol after 3 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of metoprolol is used to assess the activity of CYP2C9.
Measured: 3 weeks
Long-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.
A change in metabolic ratio of metoprolol after 12 weeks of treatment with an IL-6Ra as compared to baseline. The metabolic ratio of metoprolol is used to assess the activity of CYP2C9.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Apr 2021
- Study start25 May 2021
- Primary completion30 Sep 2022
- Study completion30 Sep 2022
Why it stopped: Slow recruitment due to COVID19.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Arthritis, RheumatoidStudies of the same condition, open and under way.
- More trials run by University of Southern DenmarkThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Southern Denmark
- Sponsor type
- University, hospital or other
- Collaborators
- Odense University Hospital, Esbjerg Hospital - University Hospital of Southern Denmark, King Christian X´Hospital for Rheumatic Diseases, Sygehus Lillebaelt, Odense Patient Data Explorative Network
- Responsible party
- Principal investigator, Ann-Cathrine Dunvald, University of Southern Denmark
- Investigators
- Ann-Cathrine Dunvald, MD, Principal investigator, University of Southern Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04842981
- Sponsor's protocol ID
- AKF-398
- Status last verified
- Jan 2023
- First submitted
- 23 Mar 2021
- Last updated
- 25 Jan 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 37831074
Study at a glance
From the registry record, last updated by the sponsor on 25 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Interleukin-6 Inhibitors and Drug-drug Interactions in Patients With Rheumatoid Arthritis
- ClinicalTrials.gov ID
- NCT04842981
- Acronym / sponsor ID
- AKF-398
- Conditions
- Arthritis, Rheumatoid, Interaction
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Slow recruitment due to COVID19.
- Enrolment
- 3 participants (actual)
- Lead sponsor
- University of Southern DenmarkUniversity, hospital or other
- Collaborators
- Odense University Hospital, Esbjerg Hospital - University Hospital of Southern Denmark, King Christian X´Hospital for Rheumatic Diseases, Sygehus Lillebaelt, Odense Patient Data Explorative Network
- Study start
- 25 May 2021 (actual)
- Primary completion
- 30 Sep 2022 (actual)
- Study completion
- 30 Sep 2022 (actual)
- First posted
- 13 Apr 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Interleukin 6 receptor antibody | Experimental | Drug: Tocilizumab, Drug: SarilumabTocilizumab, 162 mg subcutaneous, once every week OR Sarilumab, 200 mg subcutaneous, once every two weeks. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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)
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TocilizumabAlso: RoActemraTocilizumab 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. | Drug | Interleukin 6 receptor antibody |
| SarilumabAlso: KevzaraTocilizumab 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. | Drug | Interleukin 6 receptor antibody |
Primary outcome
Short-term change in CYP3A4 activity assessed by midazolam metabolic ratio.
Time frame: 3 weeks
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.
11 secondary outcomes
Long-term change in CYP3A4 activity assessed by midazolam metabolic ratio.
Time frame: 12 weeks
Short-term change in CYP1A2 activity assessed by caffeine metabolic ratio.
Time frame: 3 weeks
Long-term change in CYP1A2 activity assessed by caffeine metabolic ratio.
Time frame: 12 weeks
Short-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.
Time frame: 3 weeks
Long-term change in CYP2B6 activity assessed by efavirenz metabolic ratio.
Time frame: 12 weeks
Short-term change in CYP2C9 activity assessed by losartan metabolic ratio.
Time frame: 3 weeks
Long-term change in CYP2C9 activity assessed by losartan metabolic ratio.
Time frame: 12 weeks
Short-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.
Time frame: 3 weeks
Long-term change in CYP2C19 activity assessed by omeprazole metabolic ratio.
Time frame: 12 weeks
Short-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.
Time frame: 3 weeks
Long-term change in CYP2D6 activity assessed by metoprolol metabolic ratio.
Time frame: 12 weeks
Results and safety
The study was stopped early (reason given: Slow recruitment due to COVID19.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jan 2023.
- Derived from this study: PubMed 37831074Dunvald 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Ann-Cathrine Dunvald, MD principal investigator
University of Southern Denmark
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Tocilizumab and Sarilumab in people with Arthritis, Rheumatoid and Interaction, run by University of Southern Denmark at 3 sites in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Slow recruitment due to COVID19.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Short-term change in CYP3A4 activity assessed by midazolam metabolic ratio. (time frame: 3 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04842981, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jan 2023.