A Study to Investigate Safety, Tolerability, and PK of Oral Doses of TCK-276 in Patients With Rheumatoid Arthritis

A Phase 1, Randomized, Placebo-controlled, Double-blind, Multiple Ascending Dose Study to Investigate Safety, Tolerability, and Pharmacokinetics of Oral Doses of TCK-276 in Patients With Rheumatoid Arthritis

The study is to evaluate the safety, tolerability, and pharmacokinetic (PK) of multiple orally administered TCK-276 in both males and females with Rheumatoid Arthritis (RA).

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: TCK-276; Drug: TCK-276 Placebo

Detailed Description

This is a Phase 1, multi-center, double-blind, randomized, placebo-controlled, multiple ascending dose (MAD) study.

The study will consist of a Screening Visit (Days -1 to Day 10), Treatment duration (up to 11 days) and a Follow-up/end of treatment (EOT) visit.

This MAD study will consist of 4 cohorts of 8 patients (6 active treatment and 2 matching placebo, or a 3:1 ratio), each receiving an oral dose of TCK-276 or matching placebo for 7 days (once daily (QD) under fed condition). The first cohort will be divided into 2 subgroups to implement the sentinel dosing approach.

The study duration is approximately 42 days.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Tustin, California, United States, 92780
      • Orange County Research Center
  • Florida
    • Doral, Florida, United States, 33172
      • St. Jude Clinical Research, LLC
    • Miami, Florida, United States, 33155
      • Allied Biomedical Research Institute
    • Miami, Florida, United States, 33136
      • SouthCoast Research Center, Inc
    • Miami Lakes, Florida, United States, 33014
      • San Marcus Research Clinic, Inc.
    • Miami Lakes, Florida, United States, 33016
      • Floridian Clinical Research, LLC
    • Winter Park, Florida, United States, 32789
      • Clinical Site Partners, LLC dba CSP Orlando
  • Texas
    • Mesquite, Texas, United States, 75149
      • SMS Clinical Research, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of RA and meeting the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA.
• Patients between the ages of 18 and 64 years, inclusive, at the Screening Visit.

• Female patient must be not pregnant, not breast feeding and one of the following conditions need to apply:

  1. Of non-childbearing potential based on documented surgical treatment or post-menopausal, meaning patient had spontaneous amenorrhea for at least 12 months without alternate medical cause prior to Screening Visit and follicle stimulating hormone (FSH) > 40 U/mL at the Screening Visit.
  2. Of childbearing potential and using a highly effective method of contraception and agrees to remain on a highly effective method from the time of signing the informed consent form (ICF) until 21 days after the last dose.
• Male patient must agree to stay abstinent or must use together with his female partner(s) a form of highly effective contraceptive (failure rate of < 1% per year) from the time of signing the ICF until up to 3 months after the last dose of the study drug.
• Nonsmokers (or other nicotine use) as determined by history and by negative urine cotinine concentration at the Screening Visit and at Admission.
• Body mass index (BMI) between 18.5 and 32.0 kg/m2, inclusive, at the Screening Visit.
• Patient is required to have completed a COVID-19 vaccine regimen within no more than 5 months prior to screening to be eligible for the study.
• Permitted concomitant medications for any reason, must be on a stable dose.
• Permitted medications include: anti-malarials; nonsteroidal anti-inflammatory drugs including selective cyclooxygenase-2 inhibitors at approved dosage, and low dose oral corticosteroids; methotrexate concomitantly with folic acid or folinic acid.

Exclusion Criteria:

• Female patients who are breastfeeding or have a positive urine pregnancy test.
• Patients who are unable to eat the prescribed meals during the stay at the site; vegetarian or vegan.
• Patient has a history of significant drug allergy.
• Patient has used a study drug, any prohibited medication(s), over-the-counter (OTC) medications, vitamins, dietary and herbal supplements.
• Patient has a history of active suicidal ideation, or any psychiatric disorders that will affect the patient's ability to participate in the study.
• Patient has a current or recent history of uncontrolled, clinically significant infectious, hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic, or allergic disease.
• Patient with any of the laboratory abnormalities as per reference.
• Patient has a history of alcohol and/or drug abuse within 24 weeks.
• Patient has positive results for drug testing and breath alcohol test.
• Regular consumption of alcohol within 6 months prior to the Screening Visit.
• Patient has positive test for hepatitis B surface antigen (HBsAg), anti-hepatitis B core (HBc) antibodies, hepatitis C virus (HCV) antibody, and/or human immunodeficiency virus (HIV) antibody at Screening Visit.
• Patient has QT interval corrected for heart rate (QTc) using Fridericia's correction (QTcF) > 450 ms for males or QTcF > 470 ms for females either at the Screening Visit or Admission, based on safety 12-lead electrocardiogram (ECG). Patient has Screening or Admission ECG with second- or third-degree atrioventricular block, bundle branch block, arrhythmia (but not sinus arrhythmia or supraventricular premature beats), or illegible QT interval.
• Patient has history or evidence of cardiopathy, acute coronary syndrome, hypertrophic cardiomyopathy, myocarditis or QT prolongation syndrome.
• Patient is unwilling to abstain from drinks and foods containing alcohol, grapefruit, or caffeine
• Patient has donated blood or experienced acute blood loss (including plasmapheresis) of greater than 500 mL within 90 days prior to the first dose of study drug.
• Patients with a known immunodeficiency disorder. Have a history of a major organ transplant or hematopoietic stem cell/marrow transplant.
• Patients with infections requiring treatment or hospitalization within 14 days prior to the Screening Visit, parenteral antimicrobial therapy within 60 days prior to the Screening Visit, infected joint prosthesis; history of herpes zoster, active herpes simplex, or herpes simplex on suppressive therapy.
• Patient has a chronic hepatic disease or hepatic impairment.
• Patient has a history of Mycobacterium tuberculosis or positive interferon gamma release assay for tuberculosis (IGRA-TB) or abnormal chest X-ray (for positive IGRA-TB patients).
• Patient has a history of any lymphoproliferative disorder.
• Patient has a history of COVID-19 unless fully recovered with no sequelae for 14 days.
• Patient who had a severe course of COVID-19 (extracorporeal membrane oxygenation, mechanically ventilated).
• Patient who has recent exposure to someone who has COVID-19 symptoms or positive test result.
• Patient who has a positive reverse transcription polymerase chain reaction (RT-PCR) test for Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2).
• Patient who has clinical signs and symptoms consistent with SARS-CoV-2 infection.
• Patients may not receive any live/attenuated vaccine from 30 days prior to the Screening Visit until Day 14 Follow-up Visit.
• COVID-19 vaccine should not be given 1 week prior to the Screening Visit.
• Patients with malignancy or history of malignancy except adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. Previous treatment with total lymphoid irradiation.
• History of recurrent inflammatory joint disease other than RA or history of any other autoimmune rheumatic diseases other than Sjogren's syndrome.
• Major surgery within 30 days prior to the Screening Visit or patients with planned surgery.
• Patients who have an abnormal chest X-ray for interstitial lung disease (ILD) and/or patients with history of ILD.
• History of fainting or family history of sudden death.
• Patient has any disorder that would interfere with the absorption, distribution, metabolism or excretion of study drug.
• Patient has a history of deep vein thrombosis and/or pulmonary embolism.
• Patient has poor venous access.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; The patient will receive Dose A of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	Drug: TCK-276; Patients will receive an oral dose of TCK-276 QD under fed conditions from Day 1 to Day 7.; Other Names: Cyclin Dependent Kinase 4/6 (CDK 4/6) Inhibitor; TEI-T01276; Drug: TCK-276 Placebo; Patients will receive an oral dose of TCK-276 matching placebo QD under fed conditions from Day 1 to Day 7.; Other Names: Placebo
Experimental: Cohort 2; The patient will receive Dose B of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	Drug: TCK-276; Patients will receive an oral dose of TCK-276 QD under fed conditions from Day 1 to Day 7.; Other Names: Cyclin Dependent Kinase 4/6 (CDK 4/6) Inhibitor; TEI-T01276; Drug: TCK-276 Placebo; Patients will receive an oral dose of TCK-276 matching placebo QD under fed conditions from Day 1 to Day 7.; Other Names: Placebo
Experimental: Cohort 3; The patient will receive Dose C of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	Drug: TCK-276; Patients will receive an oral dose of TCK-276 QD under fed conditions from Day 1 to Day 7.; Other Names: Cyclin Dependent Kinase 4/6 (CDK 4/6) Inhibitor; TEI-T01276; Drug: TCK-276 Placebo; Patients will receive an oral dose of TCK-276 matching placebo QD under fed conditions from Day 1 to Day 7.; Other Names: Placebo
Experimental: Cohort 4; The patient will receive Dose D of TCK-276 or matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	Drug: TCK-276; Patients will receive an oral dose of TCK-276 QD under fed conditions from Day 1 to Day 7.; Other Names: Cyclin Dependent Kinase 4/6 (CDK 4/6) Inhibitor; TEI-T01276; Drug: TCK-276 Placebo; Patients will receive an oral dose of TCK-276 matching placebo QD under fed conditions from Day 1 to Day 7.; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number ot Participants With Treatment Emergent Adverse Events	To evaluate the safety and tolerability of multiple oral doses of TCK-276 or placebo in patients with rheumatoid arthritis (RA)	42 days (duration of study)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax: Plasma Concentrations of TCK-276 and TEI-W00595 (Metabolite)	Cmax: Plasma Concentrations of TCK-276 and TEI-W00595 with time-concentration profile	Day 1 and Day 7
Tmax: Time of Maximum Plasma Concentration Determined Directly From the Concentration-time Profile	To evaluate tmax as pharmacokinetic (PK) variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
t½: Terminal Elimination Half-life	To evaluate t½ as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
AUCtau: Area Under the Plasma Concentration-time Curve Over a Dosing Interval, Tau = 24 Hours	To evaluate AUCtau as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
AUC0-inf: Area Under the Plasma Concentration Time Curve From Pre-dose (Time 0) Extrapolated to Infinite Time	AUC0-inf:Area under the plasma concentration time curve from pre-dose (time 0) extrapolated to infinite time (Days 1 and 7)	Day 1 and Day 7
Clearance (CL)/F: Apparent Total Body Clearance (Parent Only)	To evaluate CL/F as PK variables of TCK-276 in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
Vz/F: Apparent Volume of Distribution Based on Terminal Phase (Parent Only)	To evaluate Vz/F as PK variables of TCK-276 in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
MRT0-inf: Mean Residence Time Extrapolated to Infinity	To evaluate MRT0-inf as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
Racc (Cmax): Accumulation Ratio Based on Cmax	Racc (Cmax) calculated as Cmax on Day 7/Cmax on Day 1.	Day 1 and Day 7
Racc (AUCtau): Accumulation Ratio Based on AUCtau	Racc (AUCtau) calculated as AUCtau on Day 7/AUCtau on Day 1. To evaluate Racc (AUCtau) as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
Metabolic Ratio (MR) for Cmax	Molar metabolic ratio of Cmax calculated as (Cmax [metabolite] × molecular weight of parent)/(Cmax [parent] × molecular weight of metabolite).	Day 1 and Day 7
MR for Area Under the Plasma Concentration-time Curve (AUC)Tau	Molar metabolic ratio of AUC calculated as (AUC [metabolite] × molecular weight of parent)/(AUC [parent] × molecular weight of metabolite). To evaluate MR AUC as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
MR for Area Under the Plasma Concentration-time Curve (AUC)0-inf	Molar metabolic ratio of AUC calculated as (AUC [metabolite] × molecular weight of parent)/(AUC [parent] × molecular weight of metabolite) 0-inf. To evaluate MR AUC 0-inf as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration	Day 1 and Day 7
Ae 0-24: Amount of Study Drug Excreted Unchanged in the Urine (Days 1 and 7)	Ae 0-24: Amount of study drug excreted unchanged in the urine (Days 1 and 7) over 24 hours	Day 1 and Day 7
Fe 0-24: Percentage of Study Drug Excreted Unchanged in the Urine (Days 1 and 7)	Fe 0-24: Percentage of study drug excreted unchanged in the urine (Days 1 and 7) over 24 hours	Day 1 and Day 7
Clearance Renal (CLr): Renal Clearance (Days 1 and 7)	CLr: Renal clearance Day 1 and Day 7 (24 hours)	Day 1 and Day 7
Ae 0-72: Amount of Study Drug Excreted Unchanged in the Urine (Day 7)	Ae 0-72: Amount of study drug excreted unchanged in the urine (Day 7) over a 72 hour period	Day 7 0-72 hours
Fe 0-72: Percentage of Study Drug Excreted Unchanged in the Urine	Fe 0-72: Percentage of study drug excreted unchanged in the urine on Day 7 (72 hours)	Day 7 0-72 hours

Collaborators and Investigators

• Sponsor: Teijin America, Inc.
• Collaborators: Parexel
• Investigators: Study Director: Tatyana Zubkovskaya, Medical director

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2022
• Primary Completion (Actual): July 20, 2023
• Study Completion (Actual): July 27, 2023

Study Registration Dates

• First Submitted: June 23, 2022
• First Submitted That Met QC Criteria: June 23, 2022
• First Posted (Actual): June 29, 2022

Study Record Updates

• Last Update Posted (Actual): October 15, 2024
• Last Update Submitted That Met QC Criteria: October 9, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: autoimmune disease; Multiple Ascending Dose; Disease modifying antirheumatic drugs (DMARD)
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: TCK-276-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data will be shared that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices). Proposals should be directed to clinical-trials-contact@teijinpo.com. To gain access, data requestors will need to sign a data access agreement. Data are available for 5 years at a third party website (Link to be included).
• IPD Sharing Time Frame: Beginning 3 months and ending 5 years following article publication.
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal, to achieve aims in the approved proposal.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No