TRUXIMA Concentrate for solution for infusion Ref.[7416] Active ingredients: Rituximab

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies
ATC code: L01XC02

Truxima is a biosimilar medicinal product.

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95% of all B cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalize upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the plasma as a free antigen and, thus, does not compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis.

Peripheral B cell counts declined below normal following completion of the first dose of rituximab. In patients treated for haematological malignancies, B cell recovery began within 6 months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer (up to a median recovery time of 23 months post-induction therapy). In rheumatoid arthritis patients, immediate depletion of B cells in the peripheral blood was observed following two infusions of 1000 mg rituximab separated by a 14 day interval. Peripheral blood B cell counts begin to increase from week 24 and evidence for repopulation is observed in the majority of patients by week 40, whether rituximab was administered as monotherapy or in combination with methotrexate. A small proportion of patients had prolonged peripheral B cell depletion lasting 2 years or more after their last dose of rituximab. In patients with granulomatosis with polyangiitis or microscopic polyangiitis, the number of peripheral blood B cells decreased to <10 cells/μL after two weekly infusions of rituximab 375 mg/m², and remained at that level in most patients up to the 6 month time point. The majority of patients (81%) showed signs of B cell return, with counts >10 cells/μL by month 12, increasing to 87% of patients by month 18.

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses:

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL received 375 mg/m² of rituximab as an intravenous infusion once weekly for four weeks. The overall response rate (ORR) in the intent-to-treat (ITT) population was 48% (CI 95% 41%-56%) with a 6% complete response (CR) and a 42% partial response (PR) rate. The projected median time to progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58% vs. 12%), higher in patients whose largest lesion was <5 cm vs. >7 cm in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as duration of response <3 months) relapse (50% vs. 22%). ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT.

Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test) on response to rituximab. A statistically significant correlation was noted between response rates and bone marrow involvement. 40% of patients with bone marrow involvement responded compared to 59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a stepwise logistic regression analysis in which the following factors were identified as prognostic factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky disease.

Initial treatment, weekly for 8 doses:

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for eight doses. The ORR was 57% (95% Confidence interval (CI); 41%–73%; CR 14%, PR 43%) with a projected median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months). Initial treatment, bulky disease, weekly for 4 doses In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single lesion ≥10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m2 of rituximab as intravenous infusion weekly for four doses. The ORR was 36% (CI 95% 21%–51%; CR 3%, PR 33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses:

In a multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, were re-treated with 375 mg/m² of rituximab as intravenous infusion weekly for four doses. Three of the patients had received two courses of rituximab before enrolment and thus were given a third course in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the ORR was 38% (CI 95% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for responding patients of 17.8 months (range 5.4–26.6). This compares favourably with the TTP achieved after the prior course of rituximab (12.4 months).

Initial treatment, in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicular lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m², vincristine 1.4 mg/m² up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m²/day on days 1-5) every 3 weeks for 8 cycles or rituximab 375 mg/m² in combination with CVP (R-CVP). Rituximab was administered on the first day of each treatment cycle. A total of 321 patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median follow up of patients was 53 months. R-CVP led to a significant benefit over CVP for the primary endpoint, time to treatment failure (27 months vs. 6.6 months, p<0.0001, log-rank test). The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p<0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment with R-CVP significantly prolonged the time to disease progression or death compared to CVP, 33.6 months and 14.7 months, respectively (p<0.0001, log-rank test). The median duration of response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p<0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were 80.9% for patients in the R-CVP group compared to 71.1% for patients in the CVP group.

Results from three other randomised trials using rituximab in combination with chemotherapy regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant improvements in response rates, time-dependent parameters as well as in overall survival. Key results from all four studies are summarised in table 4.

Table 4. Summary of key results from four phase III randomised studies evaluating the benefit of rituximab with different chemotherapy regimens in follicular lymphoma:

Maintenance therapy

Previously untreated follicular lymphoma:

In a prospective, open label, international, multicentre, phase III trial 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n=881), R-CVP (n=268) or R-FCM (n=44), according to the investigators' choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomised to rituximab maintenance therapy (n=505) or observation (n=513). The two treatment groups were well balanced with regards to baseline characteristics and disease status. Rituximab maintenance treatment consisted of a single infusion of rituximab at 375 mg/m² body surface area given every 2 months until disease progression or for a maximum period of two years.

After a median observation time of 25 months from randomisation, maintenance therapy with rituximab resulted in a clinically relevant and statistically significant improvement in the primary endpoint of investigator assessed progression-free survival (PFS) as compared to observation in patients with previously untreated follicular lymphoma (Table 5).

Significant benefit from maintenance treatment with rituximab was also seen for the secondary endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT) time to next chemotherapy (TNCT) and overall response rate (ORR) (Table 5). The results of the primary analysis were confirmed with longer follow-up (median observation time: 48 months and 73 months), and have been added to Table 5 to show the comparison between the 25 and 48 and 73 month follow up periods.

Table 5. Maintenance phase: overview of efficacy results rituximab vs. observation after 73 months median observation time (compared with results of primary analysis based on 25 months median observation time, and updated analysis based on 48 months median observation time):

Rituximab maintenance treatment provided consistent benefit in all predefined subgroups tested: gender (male, female), age (<60 years, ≥60 years), FLIPI score (≤1, 2 or ≥3), induction therapy (R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction treatment (CR, CRu or PR). Exploratory analyses of the benefit of maintenance treatment showed a less pronounced effect in elderly patients (>70 years of age), however sample sizes were small.

Relapsed/Refractory follicular lymphoma:

In a prospective, open label, international, multicentre, phase III trial, 465 patients with relapsed/refractory follicular lymphoma were randomised in a first step to induction therapy with either CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone; n=231) or rituximab plus CHOP (R-CHOP, n=234). The two treatment groups were well balanced with regard to baseline characteristics and disease status. A total of 334 patients achieving a complete or partial remission following induction therapy were randomised in a second step to rituximab maintenance therapy (n=167) or observation (n=167). Rituximab maintenance treatment consisted of a single infusion of rituximab at 375 mg/m² body surface area given every 3 months until disease progression or for a maximum period of two years.

The final efficacy analysis included all patients randomised to both parts of the study. After a median observation time of 31 months for patients randomised to the induction phase, R-CHOP significantly improved the outcome of patients with relapsed/refractory follicular lymphoma when compared to CHOP (see Table 6).

Table 6. Induction phase: overview of efficacy results for CHOP vs. R-CHOP (31 months median observation time):

¹ Estimates were calculated by hazard ratios
² Last tumour response as assessed by the investigator. The “primary” statistical test for “response” was the trend test of CR versus PR versus non-response (p<0.0001) Abbreviations: NA, not available; ORR: overall response rate; CR: complete response; PR: partial response

For patients randomised to the maintenance phase of the trial, the median observation time was 28 months from maintenance randomisation. Maintenance treatment with rituximab led to a clinically relevant and statistically significant improvement in the primary endpoint, PFS, (time from maintenance randomisation to relapse, disease progression or death) when compared to observation alone (p<0.0001 log-rank test).The median PFS was 42.2 months in the rituximab maintenance arm compared to 14.3 months in the observation arm. Using a Cox regression analysis, the risk of experiencing progressive disease or death was reduced by 61% with rituximab maintenance treatment when compared to observation (95% CI; 45%-72%). Kaplan-Meier estimated progression-free rates at 12 months were 78% in the rituximab maintenance group vs. 57% in the observation group. An analysis of overall survival confirmed the significant benefit of rituximab maintenance over observation (p=0.0039 log-rank test). Rituximab maintenance treatment reduced the risk of death by 56% (95% CI; 22%-75%).

Table 7. Maintenance phase: overview of efficacy results rituximab vs. observation (28 months median observation time):

The benefit of rituximab maintenance treatment was confirmed in all subgroups analysed, regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (table 7). Rituximab maintenance treatment significantly prolonged median PFS in patients responding to CHOP induction therapy (median PFS 37.5 months vs. 11.6 months, p<0.0001) as well as in those responding to R-CHOP induction (median PFS 51.9 months vs. 22.1 months, p=0.0071). Although subgroups were small, rituximab maintenance treatment provided a significant benefit in terms of overall survival for both patients responding to CHOP and patients responding to R-CHOP, although longer follow-up is required to confirm this observation.

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80 years) with diffuse large B cell lymphoma received standard CHOP chemotherapy (cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m² up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m²/day on days 1-5) every 3 weeks for eight cycles, or rituximab 375 mg/m² plus CHOP (R-CHOP). Truxima was administered on the first day of the treatment cycle.

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a median follow-up duration of approximately 31 months. The two treatment groups were well balanced in baseline disease characteristics and disease status. The final analysis confirmed that R-CHOP treatment was associated with a clinically relevant and statistically significant improvement in the duration of event-free survival (the primary efficacy parameter; where events were death, relapse or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p=0.0001). Kaplan Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm compared to 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, estimates for overall survival were 68.2% in the R-CHOP arm compared to 57.4% in the CHOP arm. A subsequent analysis of the duration of overall survival, carried out with a median follow-up duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071), representing a risk reduction of 32%.

The analysis of all secondary parameters (response rates, progression-free survival, disease-free survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The complete response rate after cycle 8 was 76.2% in the R-CHOP group and 62.4% in the CHOP group (p=0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%. In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2 microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improvements in outcome for both high- and low-risk patients according to age adjusted IPI.

Clinical laboratory findings

Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of 356 patients evaluated for HACA, 1.1% (4 patients) were positive.

Chronic lymphocytic leukaemia

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25 mg/m², cyclophosphamide 250 mg/m², days 1-3) every 4 weeks for 6 cycles or rituximab in combination with FC (R-FC). Rituximab was administered at a dosage of 375 mg/m² during the first cycle one day prior to chemotherapy and at a dosage of 500 mg/m² on day 1 of each subsequent treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had previously been treated with monoclonal antibodies or if they were refractory (defined as failure to achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 8a and Table 8b) and 552 patients (276 R-FC, 276 FC) for the relapsed/refractory study (Table 9) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55 months in the R-FC group and 33 months in the FC group (p<0.0001, log-rank test). The analysis of overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p=0.0319, log-rank test) (Table 8a). The benefit in terms of PFS was consistently observed in most patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 8b).

Table 8a. First-line treatment of chronic lymphocytic leukaemia Overview of efficacy results for rituximab plus FC vs. FC alone – 48.1 months median observation time:

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; n.a.: not applicable
* only applicable to patients achieving a CR, nPR, PR
** only applicable to patients achieving a CR

Table 8b. First-line treatment of chronic lymphocytic leukaemia Hazard ratios of progression-free survival according to Binet stage (ITT) - 48.1 months median observation time:

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6 months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit in terms of PFS was observed in almost all patient subgroups analysed according to disease risk at baseline. A slight but not significant improvement in overall survival was reported in the R-FC compared to the FC arm.

Table 9. Treatment of relapsed/refractory chronic lymphocytic leukaemia – overview of efficacy results for rituximab plus FC vs. FC alone (25.3 months median observation time):

Response rate and CR rates analysed using Chi-squared Test. NR: not reached n.a. not applicable.
* only applicable to patients achieving a CR, nPR, PR.
** only applicable to patients achieving a CR.

Results from other supportive studies using rituximab in combination with other chemotherapy regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of previously untreated and/or relapsed/refractory CLL patients have also demonstrated high overall response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity (especially myelotoxicity). These studies support the use of rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical benefit (including CR) and are supportive for rituximab re-treatment.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in all subsets of the paediatric population with follicular lymphoma and chronic lymphocytic leukaemia. See section 4.2 for information on paediatric use.

Clinical experience in rheumatoid arthritis

The efficacy and safety of rituximab in alleviating the symptoms and signs of rheumatoid arthritis in patients with an inadequate response to TNF-inhibitors was demonstrated in a pivotal randomised, controlled, double-blind, multicentre trial (Trial 1).

Trial 1 evaluated 517 patients that had experienced an inadequate response or intolerance to one or more TNF inhibitor therapies. Eligible patients had active rheumatoid arthritis, diagnosed according to the criteria of the American College of Rheumatology (ACR). Rituximab was administered as two IV infusions separated by an interval of 15 days. Patients received 2 × 1,000 mg intravenous infusions of rituximab or placebo in combination with MTX. All patients received concomitant 60 mg oral prednisone on days 2-7 and 30 mg on days 8-14 following the first infusion. The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24. Patients were followed beyond week 24 for long-term endpoints, including radiographic assessment at 56 weeks and at 104 weeks. During this time, 81% of patients, from the original placebo group received rituximab between weeks 24 and 56, under an open label extension study protocol.

Studies of rituximab in patients with early arthritis (patients without prior methotrexate treatment and patients with an inadequate response to methotrexate, but not yet treated with TNF-alpha inhibitors) have met their primary endpoints. Rituximab is not indicated for these patients, since the safety data about long-term rituximab treatment are insufficient, in particular concerning the risk of development of malignancies and PML.

Disease activity outcomes

Rituximab in combination with methotrexate significantly increased the proportion of patients achieving at least a 20% improvement in ACR score compared with patients treated with methotrexate alone (Table 10). Across all development studies the treatment benefit was similar in patients independent of age, gender, body surface area, race, number of prior treatments or disease status.

Clinically and statistically significant improvement was also noted on all individual components of the ACR response (tender and swollen joint counts, patient and physician global assessment, disability index scores (HAQ), pain assessment and C-Reactive Proteins (mg/dL).

Table 10. Clinical response outcomes at primary endpoint in Trial 1 (ITT population):

^† Outcome at 24 weeks
Significant difference from placebo + MTX at the primary time point: ***p≤0.0001

Patients treated with rituximab in combination with methotrexate had a significantly greater reduction in disease activity score (DAS28) than patients treated with methotrexate alone (Table 10). Similarly, in all studies a good to moderate European League Against Rheumatism (EULAR) response was achieved by significantly more rituximab treated patients treated with rituximab and methotrexate compared to patients treated with methotrexate alone (Table 10).

Radiographic response

Structural joint damage was assessed radiographically and expressed as change in modified Total Sharp Score (mTSS) and its components, the erosion score and joint space narrowing score.

In Trial 1, conducted in patients with inadequate response or intolerance to one or more TNF inhibitor therapies, receiving rituximab in combination with methotrexate demonstrated significantly less radiographic progression than patients originally receiving methotrexate alone at 56 weeks. Of the patients originally receiving methotrexate alone, 81% received rituximab either as rescue between weeks 16-24 or in the extension trial, before week 56. A higher proportion of patients receiving the original rituximab/MTX treatment also had no erosive progression over 56 weeks (Table 11).

Table 11. Radiographic outcomes at 1 year (mITT population):

150 patients originally randomised to placebo + MTX in Trial 1 received at least one course of RTX + MTX by one year
* p<0.05, **p<0.001. Abbreviation: NS, non significant

Inhibition of the rate of progressive joint damage was also observed long term. Radiographic analysis at 2 years in Trial 1 demonstrated significantly reduced progression of structural joint damage in patients receiving rituximab in combination with methotrexate compared to methotrexate alone as well as a significantly higher proportion of patients with no progression of joint damage over the 2 year period.

Physical function and quality of life outcomes

Significant reductions in disability index (HAQ-DI) and fatigue (FACIT-Fatigue) scores were observed in patients treated with rituximab compared to patients treated with methotrexate alone. The proportions of rituximab treated patients showing a minimal clinically important difference (MCID) in HAQ-DI (defined as an individual total score decrease of >0.22) was also higher than among patients receiving methotrexate alone (Table 12).

Significant improvement in health related quality of life was also demonstrated with significant improvement in both the physical health score (PHS) and mental health score (MHS) of the SF-36. Further, significantly higher proportion of patients achieved MCIDs for these scores (Table 12).

Table 12. Physical function and quality of life outcomes at week 24 in trial 1:

^†Outcome at 24 weeks
Significant difference from placebo at the primary time point: *p<0.05, **p<0.001 ***p≤0.0001
MCID HAQ-DI ≥0.22, MCID SF-36 PHS >5.42, MCID SF-36 MHS >6.33

Efficacy in autoantibody (RF and or anti-CCP) seropositive patients

Patients seropositive to Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide (anti-CCP) who were treated with rituximab in combination with methotrexate showed an enhanced response compared to patients negative to both.

Efficacy outcomes in rituximab treated patients were analysed based on autoantibody status prior to commencing treatment. At Week 24, patients who were seropositive to RF and/or anti-CCP at baseline had a significantly increased probability of achieving ACR20 and 50 responses compared to seronegative patients (p=0.0312 and p=0.0096) (Table 13). These findings were replicated at Week 48, where autoantibody seropositivity also significantly increased the probability of achieving ACR70. At week 48 seropositive patients were 2-3 times more likely to achieve ACR responses compared to seronegative patients. Seropositive patients also had a significantly greater decrease in DAS28-ESR compared to seronegative patients (Figure 1).

Table 13. Summary of efficacy by baseline autoantibody status:

Significance levels were defined as *p<0.05, **p<0.001, ***p<0.0001.

Figure 1. Change from baseline of DAS28-ESR by baseline autoantibody status:

Long-term efficacy with multiple course therapy

Treatment with rituximab in combination with methotrexate over multiple courses resulted in sustained improvements in the clinical signs and symptoms of RA, as indicated by ACR, DAS28-ESR and EULAR responses which was evident in all patient populations studied (Figure 2). Sustained improvement in physical function as indicated by the HAQ-DI score and the proportion of patients achieving MCID for HAQ-DI were observed.

Figure 2. ACR responses for 4 treatment courses (24 weeks after each course (within patient, within visit) in patients with an inadequate response to TNF-inhibitors (n=146):

Clinical laboratory finding

A total of 392/3095 (12.7%) patients with rheumatoid arthritis tested positive for HACA in clinical studies following therapy with rituximab. The emergence of HACA was not associated with clinical deterioration or with an increased risk of reactions to subsequent infusions in the majority of patients. The presence of HACA may be associated with worsening of infusion or allergic reactions after the second infusion of subsequent courses.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with rituximab in all subsets of the paediatric population with autoimmune arthritis. See section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis (75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator, randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day) for 3-6 months or rituximab (375 mg/m²) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80 mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%. The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission (CR) at 6 months (Table 14).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing disease (Table 15).

Table 14. Percentage of patients who achieved complete remission at 6 months (Intent-to-treat population):*

CI = confidence interval.
* Worst case imputation
^a Non-inferiority was demonstrated since the lower bound (−3.2%) was higher than the pre-determined non-inferiority margin (−20%).
^b The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 15. Complete remission at 6-months by disease status:

Worst case imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the rituximab group compared with four in the cyclophosphamide group.

Retreatment with rituximab

Based upon investigator judgment, 15 patients received a second course of rituximab therapy for treatment of relapse of disease activity which occurred between 6 and 18 months after the first course of rituximab. The limited data from the present trial preclude any conclusions regarding the efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses (i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent relapse. The efficacy and safety of rituximab in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 months. None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevance of HACA formation in rituximab-treated patients is unclear.