Trial Information

Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients Who Receive Rituximab-containing Chemotherapy and Are Previously Infected With Hepatitis B Virus

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. The secondary endpoints of this study include the incidence of hepatitis flare,
defined as a greater than 3 fold increase of serum ALT level that exceeded 100 IU/L,
the 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, during
rituximab-CHOP chemotherapy and within 1 year after the last course of rituximab-CHOP
chemotherapy.

2.3. The secondary endpoints also include progression-free survival and overall
survival for patients who receive rituximab-CHOP chemotherapy. The modality (CT scan,
MRI, etc.) and schedule of tumor measurement will be determined according to local
treatment guidelines.

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.