Prospective registration

A Phase I clinical trial evaluating the drug-drug interaction and safety of TUL01101 tablets versus Methotrexate tablets in patients with rheumatoid arthritis

A Phase I clinical trial evaluating the drug-drug interaction and safety of TUL01101 tablets versus Methotrexate tablets in patients with rheumatoid arthritis

Shengnan Zhang  

Guoping Yang/Hao Zhang 

No. 138, Tongzipo Road, Yuelu District, Changsha City, Hunan Province

No. 138, Tongzipo Road, Yuelu District, Changsha City, Hunan Province

Clinical Trial Center of the Third Xiangya Hospital of Central South University

Clinical Trial Center of the Third Xiangya Hospital of Central South University

Yes

IRB,theThird Xiangya Hospital of Central South University

Xiaomin Wang

IRB,theThird Xiangya Hospital of Central South University,138Tongzipo Road,Yuelu District,Changsha,Hunan,China

Clinical Trial Center of Third Xiangya Hospital of Central South University

138Tongzipo Road，Yuelu District，Changsha，Hunan，China

Zhuhai Federal Pharmaceutical Co., LTD

rheumatoid arthritis

Interventional study

1

Single arm 

Objective: To evaluate the pharmacokinetic (PK) interaction between oral TUL01101 tablets and methylaminosphincter tablets in patients with rheumatoid arthritis (RA). Secondary objective: To evaluate the safety of oral TUL01101 tablets and MTX tablets in patients with RA.

Subjects must meet all of the following criteria to be enrolled 1, age range from 18 to 65 years old (including both ends of the value), male and female. 2. The index (BMI= weight/height square (kg/m2)) is in the range of 19 to 26 (including the values at both ends). 3. A diagnosis of rheumatoid arthritis meets the American College of Rheumatology (ACR) classification criteria of 1987 (see Appendix 1) or the American College of Rheumatology (ACR European League Against Rheumatism (EULAR) classification criteria of 2010 (see Appendix 2). 4. Patients who took a steady dose of 10mg/ week methylacetophenin tablets during the first 4 weeks of enrollment, and could maintain the same dose during the study period according to the researchers' assessment, and were willing to stop all other drugs except the study drugs during the study period. 5. Volunteer to participate in this experiment and sign informed consent in person.

Subjects who meet one or more of the following criteria will be excluded: 1. Known history of allergic reaction to any of the ingredients and/or other similar products under study; (2) Prior use of any of the following drugs or treatments: 1) Prior use of JAK inhibitors (including not limited to tofacatib, Baritinib, Pefieitinib, upatinib, and felotinib) within 12 weeks prior to initial administration; 2) Have used traditional synthetic antirheumatic drugs (csDMARDs), including but not limited to leflunomide, sulfoazopyridine, chloroquine/hydroxychloroquine, gold preparations, penicillamine, Eramod, Discontinuation time before initial administration of the test drug < 7 drug half-lives (7 drug half-lives: 14 weeks leflunomide [elution with cholestyramide > 11 days), And the patients who stopped cholestyramine for more than 6 hours could be enrolled in the group], sulazazopyridine for 5 days, chloroquine/hydroxychloroquine, gold preparation for 30 weeks, penicillamine for 30 days, eramode for 3 days) or other drugs known to have strong immunosuppressive or immunomodulatory effects, such as tacrolimus, Pavlin, etc., used within 3 months before screening; 3) Biologically-modified antirheumatic drugs (bDMARDs) should be used within 12 weeks before the first dose or during the trial. Including but not limited to anti-tumor necrosis factor (TNF) -a antagonists, interleukin, (IL) -1 antagonists, IL-6 antagonists, anti-CD20 monoclonal antibody and T-cell co-stimulatory molecular inhibitors, etc.); 4) Use of any non-steroidal anti-inflammatory drugs (NSAIDs) or oral glucocorticoids, and stop time before the first dose <7 drug half-lives; 5) Intramuscular, intravenous or joint injection of corticosteroid drugs, or oral administration of tripterygium wilfordii, total glucoside of paeony, sinomine and other Chinese patent medicines or Chinese herbs within 4 weeks before the first administration; 6) Received interferon therapy within 4 weeks prior to the first administration, such as roxanone, galanone, Roxanone, Alferon-N, Peroxone, Avonas, betaerone, chifuzine, actimmune, Pyroxin, Andafen, Dianol, Flucontel, etc.; 7) Have received or been exposed to live epidemic surfaces or attenuated live vaccines within 4 weeks prior to initial administration or plan to receive live vaccines or attenuated live vaccines during the trial period; 8) Drugs (including prescription and over-the-counter drugs), vitamins and food supplements used within 4 weeks prior to initial administration of CYRSA as a depressant or a strong inducer (see Appendix 3); 9) Other drugs (including prescription drugs and over-the-counter drugs) are being used, and the time of drug withdrawal before the first administration is less than 7 drug half-lives; 10) Used lymphocyte depletion agents/therapy, alkylating agents, total lymphoid irradiation and other treatments within 3 months prior to screening or plan to use them during the study period; 11) Patients who had a major trauma or underwent severe surgery within 4 weeks prior to screening or who planned to undergo major surgery during the trial period; 3. Have a history or evidence of any of the following diseases 1) Have other systemic inflammatory diseases other than RA (other than secondary Sjogren's syndrome), including but not limited to juvenile chronic arthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, systemic lupus erythematosus, ankylosing spondylitis, systemic vasculitis, or active gout; 2) Those with hereditary immune deficiency diseases in their immediate family members or themselves; 3) Felty syndrome (or arthritis - granulocytopenia - splenic syndrome); 4) A clinically significant infection in the 6 months prior to screening (e.g., a history of hospitalization or parenteral antimicrobial therapy or >1 history of oral or genital eruptions, zingles, disseminated eruptions, or any infection that the investigator otherwise determined was likely to worsen as a result of study participation; Or those who have active infection at the time of screening and need antibacterial treatment; 5) Patients with a history of arthroprosthesis infection and the prosthesis is still in situ; 6)① have a previous history of tuberculosis (TB) and have not received appropriate documented treatment, or ② have been to an infected area within 2 months prior to drug administration, the infected area refers to India, Indonesia, the Philippines and Pakistan, or ③ Radiological or laboratory examination of clinical symptoms at screening suggest active TB, Or ④ positive interferon release test (IGRA, including QuantERON.TB or spot.TB) at screening and had not been treated for preventive tuberculosis for 4 weeks prior to admission; 7) Have a history of lymphoproliferative diseases or various signs or symptoms indicating current lymphoproliferative diseases; 8) Patients with or a history of malignant tumors, including solid tumors, hematologic tumors, and carcinoma in situ, except for non-metastatic basal cell carcinoma or squamous cell carcinoma of the skin, atypical hyperplasia of the cervix, or grade I cervical carcinoma in situ that has been removed and cured at least 5 years prior to screening: 9) have an uncontrolled cardiovascular, respiratory, digestive, endocrine, hematological, neurological or psychiatric disorder or any other serious and/or unstable disease or history that the investigator believes would pose a risk under the study drug administration or would interfere with the study results; 10) Have any gastrointestinal disease that may interfere with oral drug absorption, or have undergone treatment that may interfere with drug absorption (such as gastrointestinal surgery); 11) Negligent heart failure (New York Heart Association Grade II-IV), unstable angina pectoris, stroke or transient ischemic attack, myocardial infarction, persistent and clinically significant arrhythmia, coronary artery bypass grafting or percutaneous coronary intervention within 12 weeks prior to initial administration; 4. Abnormal 12-lead electrocardiogram at screening that the investigator felt was clinically significant and would pose an unacceptable risk to the patient's participation in the study (e.g. Fridericia corrects QT interval >500 msec); 5. Any abnormal examination in line with the following criteria during screening and judged by the researcher to have clinical significance; 1) Hemoglobin < 8.5g /dL (85.0g /L) 2) Total leukocyte count <3.0x10^9L; 3) Neutrophils <1.2x19^9L; 4) Platelet count < 0.7x LLN, or International Normalized ratio (INR) >1.5, or activated partial thromboplastin time > 10s; 5) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 times ULN; total bilirubin (TBIL) >1.5 times ULN; 6) Serum creatinine (CREA) >1.5 x ULN or muscle clearance (CCLR) < 50 ml/min (using the standard Cockcroft-Gault formula); 7) Any clinically significant laboratory outliers that the investigator believes may interfere with the evaluation of the results of this study. Those tested positive for hepatitis B surface antigen, hepatitis C virus antibody, human immunodeficiency virus antibody or syphilis antibody during screening; 6. Patients tested positive for hepatitis B surface antigen, hepatitis C virus antibody, human immunodeficiency virus antibody or syphilis antibody during screening; 7. Patients who have lost blood or donated more than 400 mL in the 3 months before screening, or who have received transfusion of blood or blood components; 8. Participants who have participated in clinical trials of any drug or medical device and administered it (including placebo group) within 3 months prior to screening (except subjects who have only participated in clinical trial screening without using test drugs); 9. Previous drug abuse history, or positive urine drug screening; 10. Those who smoked more than 5 cigarettes or the equivalent amount of tobacco per day within 3 months before screening, or who could not quit smoking during the trial period; 11. More than 7 drinks per week for women or more than 14 drinks per week for men (1 drink =150mL(5oz) of wine -360mL(12oz) of beer 45mL (1.5oz) during the 28 days prior to screening, Or who has taken any alcohol-containing product within 48 hours prior to first administration and tested positive for alcohol breath test at baseline visit, or who cannot abstain from alcohol during the test; 12. Taking any special diet, including grapefruit, chocolate, tea, cola, or drinking food or drinks rich in xanthine or caffeine, alcoholic drinks or other factors affecting drug absorption, distribution, metabolism, excretion and other factors within 48 hours before the first dose; 13. Participants who still need or plan to engage in vigorous physical activity or exercise during the study period; 14. Pregnant or lactating women or women of childbearing age who have positive pregnancy test results during screening; Or had a family plan during the whole period of the study and within 3 months after the study, and did not want to take one or more physical contraceptive measures during the study and within 3 months after the study; 15. Patients who cannot tolerate venipunction and have a history of fainting needle or fainting blood; 16. have special requirements for diet; 17. Other conditions deemed unsuitable for clinical trial participation by the investigator

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This trial adopts electronic data management, using an electronic data acquisition system (DAS forEDC version 6.0 or above), and the data management process is detailed in the Data Management Plan (DMP). As a guiding document for data management, the DMP is written by the data administrator (DM) and approved by the sponsor, and the data management work will be carried out according to the time, content and method defined by the DMP.