Treatment plan:
A typical course of rituximab-CHOP chemotherapy is as follows:
rituximab 375 mg/m2 i.v., day 1, cyclophosphamide 750 mg/m2 i.v., day 1, doxorubicin 50 mg/m2 i.v., day 1, vincristine 1.4 mg/m2 (maximal 2 mg) i.v., day 1, prednisolone 40 mg/m2/day p.o., day 1 to day 5.
Typically the treatment will be repeated every 3 weeks. If the patients cannot recover from chemotherapy-induced toxicity at the schedule time of the next course of treatment, modification of chemotherapy dosage or delay of chemotherapy administration will be done according to local treatment standard and will be recorded.
The use of component therapy or granulocyte colony-stimulating factor will be at the discretion of individual investigator.
Auxiliary medication, such as anti-emetics, will be given according to local treatment guidelines.
Statistical consideration:
1. Database Management Procedures
Standard module for description of standard operation procedures for data processing to ensure quality and validity of the data.
2. Presentation of Efficacy and safety Endpoints
2.1. The primary endpoint of this study is the incidence of HBV reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA, during rituximab-CHOP chemotherapy and within 1 year after the last course of rituximab-CHOP chemotherapy.
2.2. Secondary endpoints: Incidence of hepatitis , defined as a greater than 3 fold increase of serum ALT level that exceeded 100 IU/L.
Incidence of severe hepatitis, defined as a hepatitis flare with an increase of ALT to more than 10 fold of ULN or bilirubin to more than 1.5 fold of ULN.
Association between HBV reactivation and serological breakthrough (i.e., re-appearance of HBsAg) during follow-up Association between HBV reactivation and levels of anti-HBc antibodies during follow-up Association between HBV reactivation and HLA germline polymorphism (HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1) / IL28B genotype of the patients Progression-free survival and overall survival for patients who receive rituximab-CHOP chemotherapy.
3. Hypotheses and Sample Size Determination
It is estimated that in Taiwan the incidence of 'resolved' HBV infection in the general population is about 50%. A recent survey of HbsAg(-)blood donors indicated that 7% of the donors had detectable HBV DNA in serum. The incidence of diffuse large B-cell non-Hodgkin's lymphoma in Taiwan is 700-800 new patients/year (Taiwan Cancer Registry, http://crs.cph.ntu.edu.tw). We plan to enroll 150 patients in three years (50 new patients every year).
4. General Statistical considerations
4.1 Randomization and stratification
This is a single-arm study. No randomization will be done.
4.2 Analysis population
This study will enroll NHL patients with evidence of 'resolved' HBV infection. Eligible subjects must be negative for serum HBV surface antigen (HBsAg) and positive for at least one of the following in the serum: anti-core antigen (anti-HBc), anti-surface antigen (anti-HBs), or HBV DNA. Patients who receive at least 1 dose of rituximab-CHOP chemotherapy will be enrolled in to the intent-to-treat population and safety population. Patients who complete at least 1 course of rituximab-CHOP chemotherapy will be enrolled into the per-protocol analysis. The primary and secondary endpoints described in Section 2.1, 2.2, and 2.3 will be included in the per-protocol analysis.
4.3 Dropout
Taking into account 10% dropout rate, we need to enter 62 patients per year to the trial so that we may finish accrual of patients within 3 years.
4.4 Baseline
Before the first course of rituximab-CHOP chemotherapy, the baseline characteristics for each patient will be measured.
4.5 Multicenter study
This study will be conducted by all participating medical centers to the Lymphoma Disease Committee (14 centers in total). Since the rituximab-CHOP chemotherapy is the standard first-line treatment for patients with diffuse large B-cell NHL and follicular cell NHL, no center interaction on treatment is expected in this study.
4.6 Adjustment for multiple testing
Adjustment because of multiple testing is not needed in this study.
4.7 Subgroup analysis
Pre-specified subgroup analysis for the primary endpoint (HBV reactivation rate) will be done in the following sub-groups:
1. baseline HBV DNA (+) vs. HBV DNA (-);
2. baseline alanine transaminase (ALT) normal vs. abnormal.
4.8 Patient Listings
Individual patient listings should be also provided.
5. Interim analysis and data monitoring
No interim analysis is planned for this study.
6. Final Analysis
For the final statistical analysis, this section should state the specific statistical procedures described in item 6 of this section in the analysis of every primary and secondary efficacy and safety endpoint.
