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

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05437419

Enrollment

Registered

2022-06-29

Start date

2022-08-10

Completion date

2023-07-27

Last updated

2024-10-15

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Rheumatoid Arthritis

Keywords

Multiple Ascending Dose, autoimmune disease, Disease modifying antirheumatic drugs (DMARD)

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.

Interventions

DRUGTCK-276

Patients will receive an oral dose of TCK-276 QD under fed conditions from Day 1 to Day 7.

DRUGTCK-276 Placebo

Patients will receive an oral dose of TCK-276 matching placebo QD under fed conditions from Day 1 to Day 7.

Study design

Allocation

RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 64 Years

Healthy volunteers

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.

Design outcomes

Primary

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

Secondary

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

Countries

United States

Participant flow

Participants by arm

Arm	Count
Cohort 1 The patient will receive 10 mg of TCK-276 orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	6
Cohort 2 The patient will receive 25 mg of TCK-276 orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	6
Cohort 3 The patient will receive 75 mg of TCK-276 orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	6
Cohort 4 The patient will receive 175 mg of TCK-276 orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	6
Pooled Placebo Group The patient will receive matching placebo orally from Day 1 to Day 7 (once daily (QD) under fed conditions).	8
Total	32

Baseline characteristics

Characteristic	Cohort 2	Cohort 3	Cohort 4	Cohort 1	Pooled Placebo Group	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	6 Participants	6 Participants	6 Participants	6 Participants	8 Participants	32 Participants
BMI	27.605 kg/m2 STANDARD_DEVIATION 2.6567	29.278 kg/m2 STANDARD_DEVIATION 1.3073	29.438 kg/m2 STANDARD_DEVIATION 1.5542	28.035 kg/m2 STANDARD_DEVIATION 2.5991	27.219 kg/m2 STANDARD_DEVIATION 2.2859	28.247 kg/m2 STANDARD_DEVIATION 2.217
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants	5 Participants	6 Participants	5 Participants	7 Participants	28 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1 Participants	1 Participants	0 Participants	1 Participants	1 Participants	4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Height	163.03 cm STANDARD_DEVIATION 5.8745	160.167 cm STANDARD_DEVIATION 6.4936	165.533 cm STANDARD_DEVIATION 11.661	163.5 cm STANDARD_DEVIATION 3.6472	164.878 cm STANDARD_DEVIATION 5.2737	163.515 cm STANDARD_DEVIATION 6.8
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	1 Participants	2 Participants	0 Participants	0 Participants	1 Participants	4 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	5 Participants	4 Participants	6 Participants	6 Participants	6 Participants	27 Participants
Region of Enrollment United States	6 participants	6 participants	6 participants	6 participants	8 participants	32 participants
Sex: Female, Male Female	6 Participants	6 Participants	5 Participants	6 Participants	6 Participants	29 Participants
Sex: Female, Male Male	0 Participants	0 Participants	1 Participants	0 Participants	2 Participants	3 Participants
Weight	73.252 kg STANDARD_DEVIATION 6.6383	75.102 kg STANDARD_DEVIATION 5.38	80.678 kg STANDARD_DEVIATION 9.3768	74.950 kg STANDARD_DEVIATION 7.5688	73.829 kg STANDARD_DEVIATION 4.5924	75.454 kg STANDARD_DEVIATION 6.851

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6	0 / 6	0 / 6	0 / 8
other Total, other adverse events	2 / 6	2 / 6	2 / 6	1 / 6	2 / 8
serious Total, serious adverse events	0 / 6	0 / 6	0 / 6	0 / 6	0 / 8

Outcome results

Primary

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)

Time frame: 42 days (duration of study)

Arm	Measure	Value (NUMBER)
Cohort 1	Number ot Participants With Treatment Emergent Adverse Events	2 participants
Cohort 2	Number ot Participants With Treatment Emergent Adverse Events	2 participants
Cohort 3	Number ot Participants With Treatment Emergent Adverse Events	2 participants
Cohort 4	Number ot Participants With Treatment Emergent Adverse Events	1 participants
Pooled Placebo Group	Number ot Participants With Treatment Emergent Adverse Events	2 participants

Secondary