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

Study Overview
=================
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.

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

Conditions
-----------------
Rheumatoid Arthritis

Intervention / Treatment
-----------------
* Drug: TCK-276
* Drug: TCK-276 Placebo


Participation Criteria
=================
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: 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. 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 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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<br>* Patients will receive an oral dose of TCK-276 (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>Drug: TCK-276 Placebo<br>* Patients will receive an oral dose of TCK-276 matching placebo (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>|
| Experimental: Cohort 2<br>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<br>* Patients will receive an oral dose of TCK-276 (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>Drug: TCK-276 Placebo<br>* Patients will receive an oral dose of TCK-276 matching placebo (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>|
| Experimental: Cohort 3<br>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<br>* Patients will receive an oral dose of TCK-276 (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>Drug: TCK-276 Placebo<br>* Patients will receive an oral dose of TCK-276 matching placebo (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>|
| Experimental: Cohort 4<br>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<br>* Patients will receive an oral dose of TCK-276 (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>Drug: TCK-276 Placebo<br>* Patients will receive an oral dose of TCK-276 matching placebo (Dose A, B, C, and D) QD under fed conditions from Day 1 to Day 7.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events (AEs) and adverse event of special interest (AESI) | To evaluate the safety and tolerability of multiple oral doses of TCK-276 in patients with rheumatoid arthritis (RA). | From Screening to Follow-up/ End of treatment (approximately 42 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum plasma concentration determined directly from the concentration-time profile | To evaluate Cmax as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| tmax: Time of maximum plasma concentration determined directly from the concentration-time profile | To evaluate tmax as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| 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 through Day 10 | 
| AUC0-t: Area under the plasma concentration-time curve up to last measurable concentration | To evaluate AUC0-t as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| AUC0-inf: Area under the plasma concentration-time curve from pre-dose (time 0) extrapolated to infinite time | To evaluate AUC0-inf as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| MRTlast: Mean residence time up to last measurable concentration | To evaluate MRTlast as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 | 
| 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 through Day 10 | 
| 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 through Day 10 | 
| 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 through Day 10 | 
| 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 through Day 10 | 
| Metabolic ratio (MR) for Cmax | Molar metabolic ratio of Cmax calculated as (Cmax [metabolite] × molecular weight of parent)/(Cmax [parent] × molecular weight of metabolite). To evaluate MR Cmax as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| MR for area under the plasma concentration-time curve (AUC) | 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 through Day 10 | 
| Ctrough: Concentration in a dosing period defined as the pre-dose concentration of the day | To evaluate Ctrough as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| Racc (Cmax): Accumulation ratio based on Cmax | Racc (Cmax) calculated as Cmax on Day 7/Cmax on Day 1. To evaluate Racc (Cmax) as PK variables of TCK-276 and its metabolite in patients with RA after multiple ascending dose (MAD) administration | Day 1 through Day 10 | 
| 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 through Day 10 | 
| Ae: Amount of study drug excreted unchanged in the urine | To evaluate Ae as urinary PK parameters of TCK-276 in patients with RA after multiple ascending dose (MAD) administration. | Day 1 through Day 10 | 
| Fe: Percentage of study drug excreted unchanged in the urine | To evaluate Fe as urinary PK parameters of TCK-276 in patients with RA after multiple ascending dose (MAD) administration. | Day 1 through Day 10 | 
| CLr: Renal clearance | To evaluate CLr as urinary PK parameters of TCK-276 in patients with RA after multiple ascending dose (MAD) administration. | Day 1 through Day 10 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Multiple Ascending Dose, autoimmune disease, Disease modifying antirheumatic drugs (DMARD)