Clinical Trial of TQH3906 Capsules for the Treatment of Adult Patients With Moderately to Severely Active Ulcerative Colitis or Crohn's Disease

A Phase Ib Clinical Trial to Evaluate the Efficacy and Safety of TQH3906 in Adults With Moderately to Severely Active Ulcerative Colitis or Crohn's Disease

This phase will commence following dose escalation in the 24mg bid group during Phase I. Employing a 1:1:1 randomized, double-blind, placebo-controlled study design, it will evaluate the efficacy, safety, and Pharmacokinetics/Pharmacodynamics (PK/PD) characteristics of TQH3906 capsules in subjects with moderate-to-severe active ulcerative colitis. The study will include a maximum 4-week screening period, a 12-week treatment period, and a 4-week post-treatment follow-up period, enrolling a total of 105 subjects. Among these, subjects who failed conventional therapy and those who failed biologic therapy each constitute 35% of the cohort.

week treatment period, and a 4-week post-treatment follow-up period. A total of 105 subjects will be enrolled, with 50% comprising subjects who failed conventional therapy and 50% comprising subjects who failed biologic therapy.

Dose Group Design:

Group A: Placebo Group B: 32mg dose group Group C: 24mg bid dose group The specific dose will be determined based on the 48mg dose group's medication experience from Phase I and adjusted as necessary.

Inclusion Criteria:

• Age between 18-75 years (inclusive of both 18 and 75), regardless of gender.
• Diagnosed with ulcerative colitis or Crohn's disease for ≥3 months, as assessed by histological or endoscopic examination prior to screening.
• Active moderate to severe UC or CD.
• Subjects must have failed at least one of the following drug treatments for UC or CD or be intolerant: oral aminosalicylates, oral corticosteroids, immunosuppressants, biologics, etc.
• If subjects are using the following drugs for UC or CD at the time of screening, their treatment should be stabilized with oral aminosalicylates for at least 3 weeks before the first dose of the trial medication, or stabilized with oral systemic corticosteroids for at least 2 weeks before the first dose of the trial medication, and maintain a stable dose during the trial period.
• If oral aminosalicylate or combined hormone therapy has been discontinued recently, it must be discontinued for at least 2 weeks prior to the pre-randomization endoscopy.
• Subjects (including partners) are willing to voluntarily take appropriate and effective contraceptive measures from the time of screening until 3 months after the last administration of the study medication.
• Before the trial, understand in detail the nature, significance, potential benefits, possible inconveniences, and potential risks of the trial, understand the research procedures, and voluntarily sign the informed consent form.

Exclusion Criteria:

• Pregnant or lactating women.
• Lesions confined solely to the rectal segment within 15 cm of the anus.
• Subjects diagnosed with indeterminate colitis, radiation colitis, or ischemic colitis.
• Presence of severe complications such as local stricture, intestinal obstruction, intestinal perforation, major lower gastrointestinal hemorrhage, intestinal neoplastic changes or neoplastic potential, toxic megacolon; rectal/colonic polyps, or anal diseases that the investigator assesses may impact efficacy and safety evaluation.
• Subjects with current stomas, ileostomy-anal anastomoses, or fistulas, where the physician determines surgery or medical intervention may be required within 12 weeks of study entry, or where ileostomy or colostomy may be necessary.
• Subjects with extensive small bowel resection (>100 cm) or diagnosed short bowel syndrome, or requiring total parenteral nutrition.
• Subjects with documented positive Clostridium difficile toxin (C. difficile) testing or polymerase chain reaction (PCR) testing.Polymerase Chain Reaction (PCR) test. If positive, the subject may be rescreened after appropriate treatment and retested no earlier than 7 days after treatment completion.
• Patients with confirmed cytomegalovirus-associated colitis must have undergone adequate treatment for at least 3 months prior to the screening endoscopy and must be symptom-free.
• Presence of abnormal seroviral status during the screening period:

a Active hepatitis, or hepatitis B surface antigen (HBsAg) positive with Hepatitis B Virus (HBV) DNA positive, or hepatitis B core antibody (HBcAb) positive with HBV-DNA positive, or Hepatitis C Virus (HCV) antibody positive with HCV-RNA positive; b Screening-period HIV antibody positive, or prior history of HIV infection; c. Positive treponemal antibody during screening without positive treponemal serological test (RPR or TRUST).

• History of active tuberculosis during screening or prior to enrollment, or detection of latent tuberculosis infection during screening (defined as T-cell Spot of Tuberculosis (T-SPOT.0) positive without clinical manifestations). (Note: Patients with latent tuberculosis infection may initiate preventive treatment according to guidelines for 1 month. To continue in the study, patients must agree to complete the prophylactic treatment regimen during the study period, avoiding rifampin therapy.

• History of severe herpes zoster or herpes simplex infections, including but not limited to herpes encephalitis, disseminated herpes simplex, or generalized herpes zoster.

• History of severe bacterial, fungal, or viral infection requiring hospitalization with intravenous antibiotics or antiviral therapy within 2 months prior to first dosing.

• Receipt of live vaccine within 4 weeks prior to first dosing or planned administration of live vaccine during the study period.

• Development of clinically significant infection during the screening period, including but not limited to upper respiratory tract infection, lower respiratory tract infection, herpes simplex, or herpes zoster requiring antibiotic or antiviral treatment.

• Presence of any major disease or unstable clinical condition (e.g., renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, psychiatric, neurological, immunologic, or locally active infection/infectious disease) deemed by the investigator to make participation in this study inappropriate.

• Suffering from angina pectoris, arrhythmia, or congestive heart failure requiring medication, or exhibiting clinically significant abnormalities on screening ECG.

• Abnormal screening laboratory tests:

  i. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 times upper limit of normal (ULN); a Hemoglobin < 90 g/L; b White blood cell count < 3.0 × 10⁹/L; c Neutrophil count < 1.0 × 10⁹/L; d Lymphocyte count < 0.5 × 10⁹/L; e Platelet count < 100 × 10⁹/L; f Total bilirubin > 2 times ULN; g Other significant laboratory abnormalities deemed by the investigator to make the subject unsuitable for this study.

• Subjects with poorly controlled diabetes or diabetes with major complications (e.g., retinopathy or nephropathy).

• History of malignancy (including carcinoma in situ) or lymphoproliferative disorders within 5 years prior to first dosing.

• Within 8 weeks or 5 half-lives (whichever is longer) prior to the first dose, patients must have received ≤2 classes of biologics (e.g., anti-Tumor Necrosis Factor-alpha (TNF-α) agents are considered 1 class), including but not limited to anti-TNF-α and anti-α4β7 integrin agents.

• Patients who have received Janus Kinase (JAK) inhibitors or other small molecule inhibitors (excluding those targeting Tyrosine Kinase 2 (TYK2) or TYK2/JAK1) within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose may be enrolled if the washout period is satisfied.

• Previously received treatment with small-molecule drugs targeting the same TYK2 or TYK2/JAK1 target.

• Received fecal microbiota transplantation, cyclosporine, tacrolimus, mycophenolate mofetil, thalidomide, immunosuppressants, or similar medications within 4 weeks prior to first dose.

• Received any other investigational drug within 1 month or 5 half-lives (whichever is longer) prior to the first dose.

• Underwent surgery within 4 weeks prior to the first dose, or plans to undergo surgery during the study period.

• Received immunoglobulin or blood products within 4 weeks prior to the first dose.

• Use of potent CYP450 inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) within 4 weeks prior to first dose.

• Use of topical therapy (enemas or suppositories), intravenous corticosteroids, anti-UC or CD traditional Chinese medicine, anti-infective agents, or antidiarrheal medications.

• Received nonsteroidal anti-inflammatory drugs (NSAIDs) within 1 week prior to first dose (excluding topical NSAIDs and low-dose aspirin for cardiovascular protection).

• Organ transplant recipients requiring ongoing immunosuppressive therapy.

• Known allergy to any component of TQH3906 or history of severe drug hypersensitivity.

• History of substance abuse or positive urine drug screen.

• Any other reasonable medical, psychiatric, or social reason deemed by the investigator to preclude participation in this study.