Overview

A phase III multi-center randomized, double-blind and positive-controlled clinical trial for evaluating the efficacy and safety of BCG for Therapeutic Use（BCG） in the prevention of postoperative recurrence of medium/high-risk non-muscle invasive bladder cancer (NMIBC).

Eligibility

Inclusion Criteria:

• 1. Male or female patients aged ≥18 year and ≤75 year
• 2. According to the stipulations of Guidelines on Diagnosing & Treating Bladder Cancer (Edition 2022) as promulgated by National Health Commission, an initial definite diagnosis of medium/high-risk non-muscle invasive urothelial bladder cancer (T1/Ta/Tis) as confirmed by histological examination and requiring an adjuvant therapy of BCG bladder instillation；
• 3. After a thorough TURBt, all tumors should be grossly invisible. Patients requiring a second procedure are also eligible for inclusion. Those fulfilling the requirements of a second procedure may do so. Patients fulfilling the requirements of a second procedure shall meet the following criteria:
  1. Criteria of a second TURBt: 1) Initial TURBt is insufficient; 2) No muscular specimen during an initial TURBt; 3) Stage T1 tumor; 4) G3 (advanced grade) tumor, except for simple in situ tumor;
  2. A second TURBt is recommended within Weeks 2-6 after an initial procedure. It is optimal at Week 4. After TURBt until BCG bladder instillation, no other instillations are allowed except for 1st/2nd immediate instillation chemotherapeutic agents. For the last TURBt, only epirubicin is reserved for immediate instillation chemotherapy;
  3. Subjects undergoing a second TURBt and starting BCG therapy at Weeks 2-4 after a second procedure;
  4. Based upon the first/second result of histopathology examination, comprehensively evaluating whether or not a certain patient is eligible for inclusion.
• 4. A previous history of never receiving any therapy of BCG bladder instillation;
• 5. ECOG score: 0-2 points;
• 6. Clinical laboratory tests fulfilling the following features:
  1. Blood routine: Within Day 14 prior to randomization, never using any hematopoietic growth factor or blood transfusion, including absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5×109/L; platelet ≥100000/mm3 or 100×109/L; hemoglobin ≥9 g/dL.
  2. Liver function: total serum bilirubin ≤1.5× upper limit of normal (ULN); for subjects with Gilbert syndrome total serum bilirubin <3×ULN ;AST/ALT ≤2.5×ULN.
  3. Renal function: defined as estimated creatinine clearance ≥50 mL/min according to the formula of Cockcroft-Gault;
  4. Blood coagulation function: APTT ≤ 1.5×ULN and INR ≤1.5×ULN.
• 7. Capable of understanding the procedures and methods of clinical study and

  participating voluntarily after offering thorough informed consents.

Exclusion Criteria:

• 1. Current users of immune suppressants, hormones or radiotherapy and potentially causing systemic BCG-related disease responses (patients requiring an injection of matching hormones after thyroidectomy or adrenalectomy are also eligible for inclusion);
• 2. Allergic to BCG or its analogues;
• 3. Presence of active TB lesions, currently receiving an anti-TB therapy or taking any anti-TB regimen within Month 6 prior to screening;
• 4. Known or suspected intraoperative bladder perforation;
• 5. Presence of severe gross hematuria pre-dosing as judged by investigators and with a suspicion of non-healing surgical wound;
• 6. Presence of concurrent cystitis with such signs of cystic irritation as urinary frequency/urgency/pain as judged by investigators or previously receiving therapies of other bladder instillation drugs and irritating bladder signs severe enough to interfere with study evaluations;
• 7. Individuals with a previous history of such severe adverse events as BCG sepsis or systemic infections;
• 8. Complete cystic urinary incontinence is defined as using six and more pads with 24h;
• 9. Concurrently with other urogenital system tumors or other malignant solid organ tumors;
• 10. Individuals with a previous history of severe cerebrocardiovascular, pulmonary, hepatic and renal diseases or hypertension and diabetes mellitus clinically uncontrollable as judged by investigators;
• 11. Individuals with an evidence of focal advanced or metastatic muscular infiltration urothelial cancer or concurrent extra-cystic non-muscle invasive urothelial transition cell cancer;
• 12. Receiving chemotherapy, radiotherapy or immunotherapy within Week 4 prior to an initial dose (except for immediate postoperative intravesical chemotherapy);
• 13. Pregnant or lactating women;
• 14. Individuals failing to adopt effective birth control measures during study until Month 6 after the last dose;
• 15. Participating in a clinical study of another drug within Month 3 prior to screening;
• 16. Known dependents of opioids or alcohol;
• 17. Any of the following items: Positive antibodies of (HIV, treponema pallidum and acute/chronic active hepatitis B (HBsAg); copy number of HBV-DNA in peripheral blood ≥103/mL; HCV antibody positive with copy number of HCV ≥103 /mL;
• 18. Individuals with mental retardations or poor compliance;
• 19. Any circumstance potentially boosting subject risks or interfering with study implementations as judged by investigators.