Clinical trial NCT05437419: A Study to Investigate Safety, Tolerability, and PK of Oral Doses of TCK-276 in Patients With Rheumatoid Arthritis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Rheumatoid Arthritis
Keywords: Multiple Ascending Dose
autoimmune disease
Disease modifying antirheumatic drugs (DMARD)
Lead sponsor: Teijin America, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2022-06-29
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number ot Participants With Treatment Emergent Adverse Events
timeFrame: 42 days (duration of study)
Secondary outcomes:
measure: Cmax: Plasma Concentrations of TCK-276 and TEI-W00595 (Metabolite)
timeFrame: Day 1 and Day 7
measure: Tmax: Time of Maximum Plasma Concentration Determined Directly From the Concentration-time Profile
timeFrame: Day 1 and Day 7
measure: t½: Terminal Elimination Half-life
timeFrame: Day 1 and Day 7
measure: AUCtau: Area Under the Plasma Concentration-time Curve Over a Dosing Interval, Tau = 24 Hours
timeFrame: Day 1 and Day 7
measure: AUC0-inf: Area Under the Plasma Concentration Time Curve From Pre-dose (Time 0) Extrapolated to Infinite Time
timeFrame: Day 1 and Day 7
measure: Clearance (CL)/F: Apparent Total Body Clearance (Parent Only)
timeFrame: Day 1 and Day 7
measure: Vz/F: Apparent Volume of Distribution Based on Terminal Phase (Parent Only)
timeFrame: Day 1 and Day 7
measure: MRT0-inf: Mean Residence Time Extrapolated to Infinity
timeFrame: Day 1 and Day 7
measure: Racc (Cmax): Accumulation Ratio Based on Cmax
timeFrame: Day 1 and Day 7
measure: Racc (AUCtau): Accumulation Ratio Based on AUCtau
timeFrame: Day 1 and Day 7
measure: Metabolic Ratio (MR) for Cmax
timeFrame: Day 1 and Day 7
measure: MR for Area Under the Plasma Concentration-time Curve (AUC)Tau
timeFrame: Day 1 and Day 7
measure: MR for Area Under the Plasma Concentration-time Curve (AUC)0-inf
timeFrame: Day 1 and Day 7
measure: Ae 0-24: Amount of Study Drug Excreted Unchanged in the Urine (Days 1 and 7)
timeFrame: Day 1 and Day 7
measure: Fe 0-24: Percentage of Study Drug Excreted Unchanged in the Urine (Days 1 and 7)
timeFrame: Day 1 and Day 7
measure: Clearance Renal (CLr): Renal Clearance (Days 1 and 7)
timeFrame: Day 1 and Day 7
measure: Ae 0-72: Amount of Study Drug Excreted Unchanged in the Urine (Day 7)
timeFrame: Day 7 0-72 hours
measure: Fe 0-72: Percentage of Study Drug Excreted Unchanged in the Urine
timeFrame: Day 7 0-72 hours
Other outcomes:
Locations:
city: Tustin
country: United States
facility: Orange County Research Center
state: California
city: Doral
country: United States
facility: St. Jude Clinical Research, LLC
state: Florida
city: Miami Lakes
country: United States
facility: San Marcus Research Clinic, Inc.
state: Florida
city: Miami Lakes
country: United States
facility: Floridian Clinical Research, LLC
state: Florida
city: Miami
country: United States
facility: SouthCoast Research Center, Inc
state: Florida
city: Miami
country: United States
facility: Allied Biomedical Research Institute
state: Florida
city: Winter Park
country: United States
facility: Clinical Site Partners, LLC dba CSP Orlando
state: Florida
city: Mesquite
country: United States
facility: SMS Clinical Research, LLC
state: Texas
Study officials:
affiliation: Medical Director
name: Tatyana Zubkovskaya
role: STUDY_DIRECTOR
References: