Study in Subjects With Rheumatoid Arthritis to Evaluate the Effect of a Single Dose of Olokizumab on the Pharmacokinetics of Substrates for CYP1A2, CYP2C9, CYP2C19 and CYP3A4

NCT04246762 | Completed Phase 1 Results FDA Drug

• 1 other identifier: CL04041026
• Study Type: interventional
• Target: 17
• Locations: 2 countries
• Sites: 2

Brief Summary

Olokizumab (OKZ) has been shown to reverse the inhibitory effect of IL-6 on the activity of Cytochrome P450 (CYP450) isozymes CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 in vitro. The goal of the study was to assess the effect of OKZ on the pharmacokinetics (PK) of the CYP450 probe substrates, caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), and midazolam (CYP3A4) in subjects with rheumatoid arthritis (RA).

Conditions

Rheumatoid Arthritis

Keywords

moderate Rheumatoid Arthritis; severe Rheumatoid Arthritis; subcutaneous; Olokizumab; drug interaction; CYP450

Outcome Measures

Primary Outcomes (3)

• Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Infinity (AUC(0-inf)) for Caffeine, Omeprazole and Midazolam

  Area under the AUC from time zero extrapolated to infinity, calculated by linear up/log down trapezoidal summation. In case of anomalous predose concentration of greater than 5% of Cmax was indicated, the PK parameters for the affected analyte and given subject were excluded from the analyses. Since caffeine is contained in the plethora of foods and beverages, most subjects had predose caffeine concentrations on Day 1 and Day 22 that exceeded 5% of their Maximum plasma concentration (Cmax). Caffeine PK parameter calculations and analyses were performed using concentrations adjusted by subtracting the contribution of the predose caffeine levels at each postdose timepoint using the following equation: Concentration (adjusted) = Concentration (observed) - \[C predose \* exp(-k\*t)\], with 'k' representing the patient-specific elimination rate constant (λz) determined using observed caffeine concentration data on Day 1 and Day 22 and 't' representing the actual time postdose.

  Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24 (Day 2), 30 (Day 2, only caffeine) hours post-dose; Day 22: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24 (Day 23), 30 (Day 23, only caffeine) hours post-dose

• AUC From Time Zero to the Time "t" (AUC(0-last)) for S-warfarin

  Area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration, calculated by linear up/log down trapezoidal summation for S-warfarin (10 mg warfarin contains 5 mg S-warfarin)

  Day 1: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24(Day 2), 48(Day 3), 72 (Day 4), 120 (Day 6), 168 (Day 8) hours post-dose; Day 22: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24(Day 23), 48(Day 24), 72 (Day 25), 120 (Day 27), 168 (Day 29) hours post-dose

• Maximum Plasma Concentration (Cmax) for All Cocktail Substrates

  Cmax for all cocktail substrates (caffeine, omeprazole, midazolam and S-warfarin), obtained directly from the observed concentration versus time data. In case of anomalous predose concentration of greater than 5% of Cmax was indicated, the PK parameters for the affected analyte and given subject were excluded from the analyses. Since caffeine is contained in the plethora of foods and beverages, most subjects had predose caffeine concentrations on Day 1 and Day 22 that exceeded 5% of their Cmax. Caffeine PK parameter calculations and analyses were performed using concentrations adjusted by subtracting the contribution of the predose caffeine levels at each postdose timepoint using the following equation: Concentration (adjusted) = Concentration (observed) - \[C predose \* exp(-k\*t)\], with 'k' representing the patient-specific elimination rate constant (λz) determined using observed caffeine concentration data on Day 1 and Day 22 and 't' representing the actual time postdose.

  Day 1: pre-dose, 0.5 - 24, 30 (only caffeine), 48 (only S-warfarin), 72 (only S-warfarin), 120 (only S-warfarin), 168 (only S-warfarin) hours post-dose; Day 22: pre-dose, 0.5 - 24, 30 (only caffeine), 48 - 168 (only S-warfarin) hours post-dose

Secondary Outcomes (10)

• Plasma AUC(0-last) for Cocktail Parent Compounds (for Caffeine, Omeprazole and Midazolam)

  Day 1: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24 (Day 2), 30 (Day 2, only caffeine) hours post-dose; Day 22: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24 (Day 23), 30 (Day 23, only caffeine) hours post-dose

• Plasma AUC From Time Zero to Infinity (AUC(0-inf)) for Cocktail Parent Compounds (for S-warfarin)

  Day 1: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24, 48, 72, 120, 168 hours post-dose; Day 22: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 7, 12, 24, 48, 72, 120, 168 hours post-dose

• Time to Maximum Plasma Concentration (Tmax) for Cocktail Parent Compounds

  Day 1: pre-dose, 0.5 - 24, 30 (only caffeine), 48 (only S-warfarin), 72 (only S-warfarin), 120 (only S-warfarin), 168 (only S-warfarin) hours post-dose; Day 22: pre-dose, 0.5 - 24, 30 (only caffeine), 48 - 168 (only S-warfarin) hours post-dose

• Terminal Half-life (t1/2) for Cocktail Parent Compounds

  Day 1: pre-dose, 0.5 - 24, 30 (only caffeine), 48 - 168 (only S-warfarin) hours post-dose; Day 22: pre-dose, 0.5 - 24, 30 (only caffeine), 48 - 168 (only S-warfarin) hours post-dose

• Elimination Rate Constant (λz) for Cocktail Parent Compounds

  Day 1: pre-dose, 0.5 - 24, 30 (only caffeine), 48 - 168 (only S-warfarin) hours post-dose; Day 22: pre-dose, 0.5 - 24, 30 (only caffeine), 48 - 168 (only S-warfarin) hours post-dose

Study Arms (1)

Olokizumab 128 mg +Cocktail drugs

EXPERIMENTAL

All subjects have received the following treatment: Cocktail drugs (Omeprazole + Caffeine + Warfarin (+ vitamin K solution) + Midazolam) orally administered with 240 mL of water on Day 1, single subcutaneous injection of Olokizumab 128 mg administered on Day 8 and second dose of Cocktail drugs (Omeprazole + Caffeine + Warfarin (+ vitamin K solution) + Midazolam) orally administered on Day 22

Drug: Olokizumab; Drug: Omeprazole; Drug: Caffeine; Drug: Warfarin+ Vitamin K; Drug: Midazolam

Interventions

Olokizumab DRUG

Sterile solution for subcutaneous (SC) injection, 128 mg (0.8 mL injection)

Olokizumab 128 mg +Cocktail drugs

Omeprazole DRUG

Tablets, 20 mg, oral

Olokizumab 128 mg +Cocktail drugs

Caffeine DRUG

Tablets, 100 mg, oral

Olokizumab 128 mg +Cocktail drugs

Warfarin+ Vitamin K DRUG

Warfarin -Tablets 10 mg (containing 5 mg S-warfarin), oral. Vitamin K - solution for intravenous injection, 10 mg/mL ampoule, orally.

Olokizumab 128 mg +Cocktail drugs

Midazolam DRUG

Syrup, 2 mg/mL, oral

Olokizumab 128 mg +Cocktail drugs

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects willing and able to give voluntary informed consent and sign an Informed Consent Form (ICF)
• Male subjects and their female partners and female subjects of childbearing potential must agree to adhere to the contraceptive requirements for the study
• Female subjects of non-childbearing potential must be:
• Surgically sterile (i.e. bilateral tubal ligation or removal of both ovaries and/or uterus at least 6 months prior to first dosing), or
• Naturally postmenopausal (spontaneous cessation of menses) for at least 24 consecutive months prior to first dosing, with a follicle stimulating hormone level at screening of ≥40 mIU/mL.
• Body mass index of 18 kg/m2 to 29.9 kg/m2, inclusive, and body weight of 55 kg to 110 kg, inclusive, if male, and 45 kg to 100 kg, inclusive, if female.
• Subjects must have a diagnosis of adult onset RA classified by the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 revised classification criteria for RA (Aletaha et al, 2010) for at least 12 weeks prior to Screening. If the subject was previously diagnosed according to ACR 1987 criteria, the Investigator may classify the subject per ACR 2010 retrospectively, based on medical history, and using available source data.
• Subjects must have received Methotrexate (MTX), sulfasalazine, or hydroxychloroquine for at least 12 weeks prior to Day 1 and in stable dose for at least 6 weeks prior to Day 1 without significant Adverse events (AEs). Stable doses of MTX should be 10 mg to 25 mg weekly with folic acid (at least 5 mg weekly or equivalent). No significant side effects based on the Investigator's judgment should be observed during treatment by these agents. The maximum allowed doses of sulfasalazine and hydroxychloroquine are:
• Sulfasalazine: 3 g per day
• Hydroxychloroquine: 400 mg per day
• Note: The doses should remain stable and not be changed from the time of signing the ICF until the end of the treatment period (EOT, Day 29).
• Subjects must have an increased CRP at Screening (of ≥1.2 × ULN).
• Female subjects of childbearing potential must have negative pregnancy test at Screening and throughout the study until the end of study (EOS) (Day 161).

You may not qualify if:

• Diagnosis of any other inflammatory arthritis or systemic inflammatory disease (e.g., gout, psoriatic or reactive arthritis, Crohn's disease, Lyme disease, juvenile idiopathic arthritis, or systemic lupus erythematosus). Osteoarthritis is classified as a degenerative disease rather than an inflammatory disease.
• Subjects with Steinbrocker Class III or IV functional capacity (incapacitated, largely, or wholly bed ridden, or confined to a wheelchair, with little, or no self-care).
• Prior exposure to any licensed or investigational compound directly or indirectly targeting IL-6 or IL-6R within 12 months of Day 1.
• Treatment with DMARDs other than MTX, hydroxychloroquine, or sulfasalazine. Treatment with the following DMARDs are not allowed within the specified time period prior to Day 1:
• weeks for azathioprine, cyclosporine, chloroquine, gold, penicillamine, minocycline, or doxycycline.
• weeks for leflunomide unless the subject has completed the following elimination procedure at least 4 weeks prior to Day 1: Cholestyramine at a dosage of 8 grams 3 times daily for at least 24 hours or activated charcoal at a dosage of 50 grams 4 times a day for at least 24 hours.
• weeks for cyclophosphamide.
• Treatment with any cell-depleting therapies including anti-cluster of differentiation (CD)20 or investigational agents (eg, CAMPATH®, anti-CD4, anti-CD5, anti-CD3, and anti-CD19) with the exception of rituximab. Treatment with rituximab is not allowed within 6 months of Day 1.
• Treatment with Tumor necrosis factor alpha inhibitor (TNFi) (including investigational proposed or licensed biosimilars) or any other biologic therapy for the treatment of RA within 12 weeks of Day 1.
• Use of parenteral or intra-articular glucocorticoids within 4 weeks prior to Day 1.
• Use of oral glucocorticoids greater than 10 mg/day prednisone (or equivalent) or change in dosage within 4 weeks prior to Day 1.
• Use of indomethacin and ketorolac; other nonsteroidal anti-inflammatory drugs (NSAIDs) (with the exception of aspirin, see below) must be taken at a stable dose and route of administration for at least 2 weeks prior to Day 1.
• Female subjects of nonchildbearing potential taking hormone replacement therapy within 4 weeks prior to Day 1.
• Vaccination with live vaccines in the 6 weeks prior to Day 1 or planned vaccination with live vaccines during the study.
• Participation in any other investigational drug study within 30 days or 5 times the t1/2 of the investigational drug, whichever is longer, prior to Day 1.

Sponsors & Collaborators

• R-Pharm International, LLC: lead
• IQVIA Pvt. Ltd: collaborator
• Thermo Fisher Scientific FS: collaborator

Study Sites (2)

Comac Medical Ltd

Sofia, 1618, Bulgaria

Location

ICS ARENSIA Exploratory Medicine SRL, a daughter company of ARENSIA Exploratory Medicine GmbH,Republican Clinical Hospital

Chisinau, MD2025, Moldova

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

olokizumab; Omeprazole; Caffeine; Midazolam

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

2-Pyridinylmethylsulfinylbenzimidazoles; Sulfoxides; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Xanthines; Alkaloids; Purinones; Purines; Benzodiazepines; Benzazepines

Results Point of Contact

• Title: Marina Beloukhova, Scientific advisor
• Organization: R-Pharm

beloukhova@rpharm.ru

0074959567937

Study Officials

• Mikhail Samsonov

  Chief Medical Officer, R-Pharm

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 27, 2020
• First Posted: January 29, 2020
• Study Start: November 16, 2021
• Primary Completion: June 8, 2022
• Study Completion: October 26, 2022
• Last Updated: August 15, 2024
• Results First Posted: August 15, 2024

Record last verified: 2024-03

Locations

BU (1); MO (1)