A Phase II Study of H021 Enteric-coated Tablets for Moderately to Severely Active Crohn's Disease

Inclusion criteria

• Age ≥18 years to ≤75 years, regardless of gender;
• Diagnosis of Crohn's disease (CD) ≥12 weeks prior to screening, with endoscopic and histopathological evidence required for CD confirmation. If no histological results are available at screening, biopsy results from the screening period may be used;
• Have active moderately to severely active CD, defined as: CDAI score between 220 and 450 (inclusive), and evidence of active mucosal inflammation (involving at least the ileum and/or colon) confirmed by ileocolonoscopy (central reading) performed during the screening period, with a Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥6 for ileocolonic or colonic disease (SES-CD ≥4 for isolated ileal disease);
• Inadequate response, loss of response, or intolerance to one or more of the following treatments (including corticosteroids, immunosuppressants [azathioprine, 6-mercaptopurine, methotrexate], and advanced therapies such as anti-TNF, anti-integrin, anti-IL-23 or anti-IL-12/23, JAK inhibitors) (failure to 5-aminosalicylic acid [5-ASA] alone does not meet the study inclusion requirements) (it will be determined by the investigator based on the assessment criteria; see Appendix 13.1 for details);
• If the patient is using the following medications for CD at screening, they must have been on stable treatment during the screening period and the requirements during the study are as follows:

• Oral 5-aminosalicylic acid (5-ASA) stable treatment for ≥2 weeks prior to screening endoscopy and must remain stable during the study;
• Oral corticosteroids equivalent to prednisone dose ≤20 mg/day or budesonide ≤9 mg/day, stable for ≥2 weeks prior to endoscopy during screening and must remain stable during the double-blind induction treatment period;
• Oral immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate) stable treatment for ≥4 weeks prior to screening endoscopy and must remain stable during the study. Patients taking methotrexate are advised to supplement with folic acid (specific dose determined by the investigator) unless contraindicated;
• Female participants must meet one of the following conditions:

• Postmenopausal status: Postmenopausal is defined as the absence of menstruation for at least 12 consecutive months without other medical explanation. For women not using hormonal contraception or hormone replacement therapy (HRT), menopausal status can be confirmed by detecting follicle-stimulating hormone (FSH) levels within the menopausal range.

Note: For women receiving HRT whose menopausal status is uncertain, if they wish to continue HRT during the study, a highly effective non-estrogen-containing hormonal contraceptive method must be used (see Section 7.4.1.8).

Or

• Permanent infertility: including but not limited to hysterectomy, bilateral salpingectomy, or bilateral oophorectomy.

Or

• Women of childbearing potential: May only be enrolled if they and their non-sterilized male sexual partner agree to consistently use highly effective contraception (as defined in Section 7.4.1.8) from the time of signing the informed consent form until at least 30 days after the last dose of study treatment.

Note: A woman of childbearing potential is defined as a woman who has experienced menarche, is premenopausal, and has not undergone permanent sterilization. The use of contraceptive methods must comply with the relevant regulations regarding contraceptive requirements for clinical studies in the region where the participant is located.

• Female participants must not be pregnant or breastfeeding from the screening period until 30 days after the last dose of study treatment (or longer as required by local regulations), and must have no plans to become pregnant or donate eggs.

Male participants:

• Male participants who have not undergone vasectomy and whose sexual partner is a woman of childbearing potential must agree to use acceptable contraception (see Section 7.4.1.8) from the first dose until at least 90 days after the last dose.
• Male participants must have no plans to father a child or donate sperm during the study and for 90 days after the last dose of study treatment.
• Voluntarily sign the ICF, willing and able to comply with all planned visits, treatment plan, study assessments (including endoscopy and daily diary entry), laboratory tests, lifestyle considerations, and other study procedures.

Exclusion criteria

• History of allergy to any component of the investigational product (including the investigational drug and placebo);
• Study participants who have previously received treatment that upregulates microRNA-124 (miR-124) (e.g., ABX464);
• Study participants who have failed more than three advanced therapies for CD, or who have failed two advanced therapies for CD with different mechanisms of action;
• Treatment with cyclosporine, tacrolimus, sirolimus, mycophenolate mofetil, or thalidomide within 4 weeks prior to screening endoscopy;
• Treatment with biologics (e.g., anti-TNF, anti-integrin, anti-IL-23 or anti-IL-12/23) within 8 weeks prior to screening endoscopy or within 5 half-lives of the drug (whichever is longer);
• Study participants who have previously received natalizumab (or any other α4β1 integrin antagonist) treatment;
• Treatment with small-molecule targeted drugs (e.g., upadacitinib) within 4 weeks prior to screening endoscopy or within 5 half-lives of the drug (whichever is longer);
• Treatment with intravenous medium- to high-dose corticosteroids (e.g., methylprednisolone 60 mg/day or hydrocortisone 300 mg/day) within 2 weeks prior to screening endoscopy;
• Discontinuation of oral immunosuppressants (azathioprine, 6-mercaptopurine, methotrexate) within 4 weeks prior to screening endoscopy, or discontinuation of oral 5-ASA or oral corticosteroids within 2 weeks prior to screening endoscopy;
• Treatment with rectal aminosalicylate preparations or corticosteroids, other enemas/suppositories (except those required for endoscopy) within 2 weeks prior to screening endoscopy;
• Total enteral nutrition or total parenteral nutrition, or fecal microbiota transplantation within 4 weeks prior to screening endoscopy;
• Known symptomatic intestinal strictures and/or inability to pass the endoscope due to stricturing lesions;
• Evidence or clinical suspicion of other forms of inflammatory bowel disease (ulcerative colitis, indeterminate colitis) or concurrent other active gastrointestinal inflammatory diseases (including but not limited to infectious colitis, ischemic colitis, radiation colitis, microscopic colitis, and uncontrolled celiac disease);
• Presence of untreated active external fistula or perianal fistula or abscess at screening. Patients with stable fistulas without abscess and with minimal or no drainage may be enrolled. For recent skin abscesses and perianal abscesses, if drainage and treatment have been completed at least 3 weeks prior to screening colonoscopy (at least 8 weeks for intra-abdominal abscesses) and no further surgery is anticipated, inclusion is allowed;
• Conditions related to CD surgery at screening:

• Current ostomy or ileal pouch;
• Absence of more than 2 of the following 5 complete intestinal segments: terminal ileum, right colon, transverse colon, left colon, and sigmoid colon and rectum;
• Previous small bowel resection with total length >100 cm or short bowel syndrome;
• Intestinal resection surgery within 3 months prior to baseline;
• Any other manifestation that may require surgery during the study period;
• Study participants with evidence of colonic dysplasia (excluding completely resected low-grade dysplasia lesions), adenoma (excluding completely resected colonic adenomatous polyps), or neoplasia;
• History of lymphoproliferative disorders, including lymphoma, or symptoms or signs suggestive of possible lymphoproliferative disorders, such as lymphadenopathy and/or splenomegaly;
• History of malignancy in the past 5 years (participants with basal cell carcinoma, localized squamous cell carcinoma of the skin, or carcinoma in situ of the cervix may enter this study if they have been cured for at least 12 months prior to signing the ICF);
• Presence of unstable or poorly controlled diseases, including but not limited to cardiovascular, cerebrovascular, respiratory, gastrointestinal (except CD), hepatic, renal, endocrine, hematologic, or neurological diseases, which may affect patient safety in the study or confound efficacy assessments;
• History of acute myocardial infarction or unstable angina, severe arrhythmia (multifocal frequent ventricular premature beats, ventricular tachycardia, ventricular fibrillation) within the past 6 months; New York Heart Association (NYHA) functional class III-IV. Study participants with a family or personal history of congenital or acquired long QT syndrome, or with significantly prolonged QTc interval at baseline (QTcF >450 msec for male study participants, QTcF >470 msec for female study participants);
• Abnormal serological virology tests, including any of the following:

• Positive for hepatitis B surface antigen (HBsAg);
• Positive for hepatitis B core antibody (HBc Ab) with detectable HBV-DNA;
• Positive for hepatitis C antibody (HCV-Ab) (study participants who have been successfully treated and are ≥1 year post-treatment without recurrence and with undetectable HCV RNA are eligible for this study);
• Positive for human immunodeficiency virus antibody (HIV-Ab) or Treponema pallidum antibody (TP-Ab);
• Active tuberculosis or latent tuberculosis without prophylactic treatment (for those with latent tuberculosis infection, those receiving prophylactic treatment may be enrolled); or study participants with a history of tuberculosis not fully cured;
• Positive Clostridioides difficile test at the screening visit; if Clostridioides difficile is positive, the study participant may be treated and retested ≥2 weeks after completing treatment;
• Study participants with chronic or recurrent Grade 3 or 4 infection within 2 months prior to screening or with a history of opportunistic infection during periods without immunosuppressive therapy; herpes zoster reactivation within 2 months prior to screening; active infection at screening, or any severe infection episode requiring hospitalization or intravenous antibiotics within 1 month prior to screening or during screening (fungal infection of the nail bed is acceptable);
• Any other history of infection that, in the investigator's opinion, may worsen if the study participant participates in the study;
• Abnormal laboratory tests during screening, including any of the following:

• Neutrophil count <0.75x109/L;
• Hemoglobin ≤80 g/L;
• Platelet count <100x109/L;
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 times the upper limit of normal (ULN);
• Total bilirubin >1.5 times ULN (if the direct bilirubin fraction is <35%, isolated bilirubin >1.5×ULN is acceptable); Participants with isolated indirect hyperbilirubinemia consistent with Gilbert's syndrome may be enrolled if other hepatic function parameters are within acceptable limits;
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula without race adjustment (the calculation method is presented in 13.2);
• History of organ transplantation requiring ongoing immunosuppressive therapy;
• Receipt of any live vaccine within 3 months prior to randomization; or planned receipt of any live vaccine during the study;
• Contraindications to colonoscopy;
• History of drug abuse or alcohol abuse/dependence;
• Suspected or confirmed pregnancy, or lactating female;
• Participation in another drug/device clinical study and use of the investigational drug/device within 3 months prior to randomization;
• Any other condition that, in the investigator's opinion, makes the participant unsuitable for participation in this study;
• Treatment with a narrow therapeutic index CYP1A2 substrate drug (e.g., clozapine, theophylline, ropinirole, warfarin, methadone) within 5 half-lives prior to the start of study treatment