Rituximab in Combination with Corticosteroids for the Treatment of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A NICE Single Technology Appraisal

Cyclophosphamide (CYC) in combination with glucocorticoids (usually prednisolone) represents the mainstay of remission induction treatment for generalized and severe AAV [34]. There is currently no universal agreement as to whether treatment should be with oral CYC (2 mg/kg per day, for up to 6 months) or intravenous pulses following the CYCLOPS regimen (15 mg/kg every 2 weeks for three pulses, followed by the same dose administered at 3-week intervals, for up to 6 months). Typically, treatment with intravenous pulses is thought to lead to a lower risk of side effects but may lead to a higher risk of relapse [34]. While CYC represents the standard of care for patients with moderate or severe AAV, other treatments, such as mycophenolate mofetil or methotrexate, may be used in patients who are intolerant of CYC or who do not wish to receive it. Those treatments have been investigated in generally less severely affected AAV patients [36, 37], and their effectiveness in patients with severe AAV is unknown.

Once patients have been induced into remission, they generally receive remission maintenance therapy with a combination of low-dose glucocorticoid therapy and azathioprine (2 mg/kg per day for at least 24 months) [34]. Leflunomide (20–30 mg per day) or methotrexate (20–25 mg/kg per week) are also sometimes used for remission maintenance [34].

The introduction of CYC treatment in the 1970s resulted in a significant reduction in mortality associated with the disease. However, considerable morbidity associated with both the disease and the treatment remains. In patients who are successfully induced into remission, up to 50 % will relapse within 5 years, and each relapse carries a risk of subsequent critical organ damage [27, 28]. Therapies used to treat AAV are themselves also associated with substantial toxicities, which frequently result in severe and permanent patient morbidity and mortality [38]. In particular, treating AAV with CYC can lead to opportunistic infections, bone marrow suppression, hemorrhagic cystitis, infertility and cancer—particularly haematopoietic and bladder malignancies [39, 40]. There are also substantial morbidities associated with a repeated and prolonged course of glucocorticoids. Infections are a well-known complication of glucocorticoids, especially in the treatment of vasculitis [41]. Other known complications of steroid therapy include new-onset diabetes, osteoporosis, avascular necrosis, peptic ulcers and cataracts [42].

RTX, a genetically engineered chimeric mouse/human monoclonal antibody, received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use in March 2013 for the indications of GPA and MPA [43]. The indicated RTX dose is 375 mg/m², administered as an intravenous infusion once per week for 4 weeks, although a 2 × 1,000 mg dose administered on day 1 and day 15 of the treatment cycle is widely used off-label in the UK for AAV. RTX should be combined with glucocorticoid treatment [44].

NICE issued a final scope to appraise the clinical effectiveness and cost effectiveness of RTX for treatment of patients with AAV. The decision problem addressed in the manufacturer’s submission differed slightly from the NICE scope, because of the slightly more restrictive nature of the drug’s indication. The appraisal considered treatment with RTX in combination with corticosteroids for induction of remission in patients with severe AAV (MPA or GPA), compared with alternative treatment strategies. The outcome measures that were included were mortality, the remission rate and the duration of remission, relapse rates, the cumulative dose of immunosuppressants, adverse events (AEs) and health-related quality of life (HRQoL). An economic evaluation expressing the cost effectiveness of RTX in terms of an incremental cost per quality-adjusted life-year (QALY) gained was submitted to NICE by the manufacturer.

The clinical effectiveness evidence in the submission was based predominantly on data from two randomized, controlled trials. RAVE was a multicentre, randomized, placebo-controlled, double-blind, double-dummy, noninferiority trial, which compared RTX (375 mg/m² per week for 4 weeks) and CYC (2 mg/kg per day) for induction of remission in 197 patients with new or relapsed severe MPA or GPA [35]. The Randomized Trial of Rituximab Versus Cyclophosphamide in ANCA-Associated Vasculitis (RITUXVAS) was a phase II, open-label, randomized, controlled, prospective study, which evaluated RTX (375 mg/m² per week for 4 weeks) combined with two intravenous doses of CYC (15 mg/kg given with the first and third RTX doses), compared with the CYCLOPS intravenous CYC regimen (15 mg/kg for 3–6 months, 6–10 doses in total) in 44 patients with newly diagnosed severe AAV [45]. In both studies, patients in the CYC control group received azathioprine as remission maintenance therapy, whereas patients in the RTX group received no remission maintenance therapy. The manufacturer gave precedence to data from the RAVE trial because this reflected the regimen sanctioned in the market authorization, presenting data from RITUXVAS as supporting evidence.

In RAVE, the primary endpoint was remission of disease without use of prednisone at 6 months; glucocorticoids were tapered off, such that all patients who had remission without disease flares had discontinued glucocorticoids by 5 months. Remission was signified by a Birmingham Vasculitis Activity Score for WG (BVAS/WG) [46] of 0. Secondary endpoints included the rates of disease flares, a BVAS/WG of 0 with less than 10 mg per day of prednisone use, the cumulative glucocorticoid dose, rates of AEs, and HRQoL measured using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) [47]. A disease flare was defined as an increase in the BVAS/WG of ≥1 point.

The manufacturer reported the results of the RAVE trial, which are published elsewhere [35]. The trial demonstrated noninferiority of RTX compared with CYC because the lower bound of the 95 % confidence interval for the primary endpoint was higher than the pre-determined noninferiority margin of −20% (p < 0.001). Sixty-three patients (63.6 %) in the RTX group achieved complete remission, compared with 52 patients (53.1 %) in the CYC group, an absolute difference of 10.6 % (95 % confidence interval [CI] −3.2 to 24.3 %, p = 0.132), hence a statistically significant advantage associated with RTX was not observed. Statistically significant changes in the secondary efficacy endpoints measured in RAVE were not observed, other than in exploratory subgroup analyses [35]. Exploratory subgroup analysis of complete remission in newly diagnosed patients gave an absolute difference of −4.2 % (95 % CI −23.6 to 15.3 %, p = 0.673) in favour of CYC (60.4 % in the RTX group compared with 64.6% in the CYC group). A similar analysis in patients with recurrent disease gave a statistically significant absolute difference of 24.7 % (95 % CI 5.8 to 43.6 %, p = 0.013) in favour of RTX (66.7 % in the RTX group compared with 42.0 % in the CYC group).

In RITUXVAS, the primary endpoints were sustained remission (defined as an absence of disease activity [BVAS = 0] for at least 6 months) and the rates of severe AEs at 12 months. Sustained remission occurred in 25 of 33 patients in the RTX group (76 %) and in 9 of 11 patients in the control group (82 %). The absolute difference in sustained remission with RTX as compared with CYC was −6 percentage points (95 % CI −33 to 21, p = 0.68). Among the patients who remained alive at 12 months, 93 % of the patients in the RTX group and 90 % of those in the control group had sustained remission (p = 0.80). There were no significant differences between the treatment arms for any of the secondary efficacy outcomes, such as the median time to remission, the median BVAS and the prednisone doses.

The manufacturer submitted evidence on the safety of RTX, focussed on 18 months of data collected in RAVE. There were no reported significant differences between the treatment groups in almost all AE outcomes, but there were some notable disparities regarding leucopenia and malignancies. More patients in the CYC group than in the RTX group (32 [33 %] versus 22 [22 %], p = 0.01) had one or more of the predefined selected AEs (including death, malignant conditions, grade 2 or higher leucopenia or thrombocytopenia, grade 3 or higher infections, drug-induced cystitis, venous thromboembolic events, stroke, hospitalizations and infusion reactions that contraindicated further infusions), but more episodes of grade 2 or higher leucopenia in the control group (10 versus 3) accounted for most of this difference. Malignant conditions developed in 7 patients after 6 months: 6 of 124 patients (5 %) who were exposed to RTX at any point during the trial (including after 6 months), as compared with 1 of 73 patients (1 %) without exposure to RTX (p = 0.26).

The manufacturer presented limited safety results from the RITUXVAS trial, but the ERG noted that a total of 31 severe AEs had occurred in 14 of the 33 patients in the RTX group (42 %), and 12 severe AEs had occurred in 4 of the 11 patients in the control group (36 %). The incidence rates of severe AEs did not differ significantly between the groups (p = 0.77). Six of the 33 patients in the RTX group (18 %) and 2 of the 11 patients in the control group (18 %) died (p = 1.00). The causes of death were infections (in 3 patients in the RTX group and in 1 patient in the control group), cardiovascular disease (in 1 patient in the RTX group and in 1 patient in the control group), and complications of end-stage renal failure (in 2 patients in the RTX group).

The manufacturer conducted a systematic review on the cost effectiveness of one or more interventions for patients with AAV. No suitable studies were found, and the manufacturer therefore submitted a de novo model-based economic evaluation, which assessed the cost effectiveness of different treatment strategies for patients with AAV. Separate analyses were undertaken for patients with newly diagnosed AAV, people with recurrent AAV, all patients (including both newly diagnosed and relapsed patients) and patients intolerant of CYC. The model was constructed using a cohort Markov approach with a 6-month cycle length. Patients entered the model at an age of 52.8 years, based upon the mean age at baseline in the RAVE trial. A lifetime time horizon was modelled. Health states were included for remission, non-remission, uncontrolled disease and death (Fig. 1). The structure of the model is outlined in the ERG report [2].

Model parameter values for response rates were primarily taken from the RAVE trial. However, the model incorporated various treatment sequences, including two courses of CYC and RTX for selected patients, and for some sequences, data were not available from RAVE, and so assumptions were made. For each subgroup that was modelled, the relevant response rate was taken from RAVE where possible—RAVE provided data on response rates for CYC and RTX in the treatment-naïve subgroup, the recurrent-disease subgroup and all patients. For the recurrent-disease subgroup, no data on remission rates associated with a second course of CYC could be derived from the RAVE trial, and no data were available on the remission rates associated with a second course of RTX. The manufacturer assumed reduced response rates for these parameters.

The relapse rates used in the manufacturer’s model were derived from the RAVE trial. Exponential models were fitted to flare data from patients who had experienced remission at 6 months, in order to estimate the time-to-event for relapse. The same relapse rate was applied after different courses of treatment within each subgroup analysis, but different relapse rates were used in each subgroup.

Age- and sex-specific mortality risks were based upon UK life tables [56], adjusted according to the age and gender distributions in the RAVE trial and a published standardized mortality ratio (SMR) comparing a general population with an AAV population [57]. The AAV SMR was applied directly to the non-remission health state, and the SMR was arbitrarily altered by ±10 % to reflect mortality in the remission and uncontrolled-disease states.

Utility scores were based upon UK evidence for the general population [58], adjusted according to the RAVE trial demographics and weighted for remission (weight = 0.98) and non-remission (weight = 0.88) health states, according to SF-36 data (subsequently transformed into EQ-5D utility scores) collected from the RAVE trial. An additional utility decrement was applied to patients in the uncontrolled-disease health state (weight = 0.79), assuming that the difference between the non-remission and uncontrolled-disease health states is the same as the difference between the remission and non-remission health states. Further decrements were made according to the probability of experiencing AEs in each health state. The AE rates were based upon data from RAVE and included anaemia, leucopenia, deep vein thrombosis, dyspnoea, diarrhoea and pneumonia. The costs of managing these AEs were based upon relevant costs taken from the NHS Trusts reference costs schedules for 2009–2010 [59].

Drug acquisition costs were taken from British National Formulary No. 64 [60] and were based upon licensed doses, apart from glucocorticoid costs, which were based upon the average dose used in the RAVE trial. Administration costs for RTX and intravenous CYC were assumed to be equal and were based upon a previous economic evaluation of infliximab [61]. Monitoring costs were included for oral CYC and for patients receiving azathioprine maintenance therapy. Regular outpatient appointments with relevant consultant specialists were also assumed, the frequency of which differed across health states—notably, once patients were in the uncontrolled-disease health state, it was assumed that they attended one specialist palliative care outpatient appointment every 1.5 weeks for all remaining years of life. The costs of these appointments were valued using NHS reference costs.

The results from the manufacturer’s base-case analysis are shown in Table 1. These results represent those provided by the manufacturer after it responded to clarifications requested by the ERG, as some amendments were made to the economic model. They indicate that the RTX treatment strategy results in an incremental cost-effectiveness ratio (ICER) of £8,544 per QALY gained for all patients, but in the treatment-naïve and recurrent-disease subgroups, the ICERs were £55,175 per QALY gained and £43,003 per QALY gained, respectively. In the CYC-intolerant subgroup analysis, RTX dominated the comparator, which was deemed to represent best supportive care. The manufacturer undertook probabilistic sensitivity analysis but did not report the probabilistic ICERs. For the all-patients analysis, the manufacturer reported that the probabilities of the RTX treatment sequence being cost effective, compared with the CYC treatment sequence, were 61.7 % and 64.6 % for cost-effectiveness thresholds of £20,000 and £30,000 per QALY gained, respectively. The manufacturer presented several deterministic sensitivity analyses and found that the results of the all-patients analysis were relatively insensitive to variations in the tested model input parameters, with the exception of (i) the CYC remission rate; (ii) the uncontrolled-disease utility; (iii) the frequency of consultant visits in each health state; and (iv) the reference cost applied to the consultant appointments in the uncontrolled-disease health state. In addition, several structural sensitivity analyses were presented, testing different numbers of CYC and RTX courses for different patient groups. As would be expected, the results were highly sensitive to these structural assumptions.

The ERG amended the identified technical errors in the manufacturer’s model, amended several parameter value estimates to better reflect reality (particularly for the uncontrolled-disease health state) and amended the modelled treatment sequences to allow for fully incremental analyses of introducing RTX into the treatment sequence either before or after CYC. The cost-effectiveness results for all patients and for the treatment-naïve, recurrent-disease and CYC-intolerant subgroups are shown in Table 2.

The additional work undertaken by the ERG indicated that including RTX in the treatment sequence increases health benefits, compared with the current standard treatment sequence (that is, a treatment sequence that does not include RTX). In the analyses for all patients, the treatment-naïve subgroup and the recurrent-disease subgroup (for patients who are eligible for further CYC treatment), the ICER associated with adding RTX after CYC treatment had been exhausted was in the range of £11,129 to £12,851 per QALY gained. However, in each of these analyses, the ICERs associated with administering RTX earlier in the treatment sequence were greater than £50,000 per QALY gained—sometimes substantially so. It is particularly important to note the substantial reductions in total lifetime costs resulting from the ERG’s amended model, compared with the manufacturer’s original model (the manufacturer estimated lifetime costs in the region of £100,000 per patient, compared with the ERG’s estimates of around £20,000). This is almost entirely due to the apparent substantial overestimation of costs associated with the uncontrolled-disease health state in the manufacturer’s original model.

In the recurrent-disease subgroup (for patients who are ineligible for further CYC treatment) and in the CYC-intolerant subgroup, the ICER associated with treating patients with RTX rather than best supportive care was in the range of £10,699 to £11,277 per QALY gained. In these scenarios (and in all other scenarios), best supportive care represents continued treatment to maintain patients in a state of low-grade ‘grumbling’ disease. The ERG noted that while these analyses were useful, they were limited and may represent underestimates of the true ICER because relevant comparators such as mycophenolate mofetil were not included in the model.

On the basis of the clinical evidence provided in the manufacturer’s submission, RTX given at a dose of 4 × 375 mg/m² has an effectiveness and safety profile similar to that of oral CYC in terms of induction of remission in adults with AAV and de novo disease. For patients who have relapsed once on CYC, RTX appears to be more effective than oral CYC in terms of inducing remission in adults with generalized, severe AAV. However, the submitted evidence was limited because it included only one trial that incorporated the licensed regimen, and it did not include evidence on long-term safety and effectiveness.

The ERG could not offer robust estimates of the likely cost effectiveness of RTX based upon the original version of the manufacturer’s economic model. Several amendments had to be made. On the basis of the ERG’s amended version of the manufacturer’s economic model, RTX appeared to represent a cost-effective addition to the treatment sequence at a cost-effectiveness threshold of £20,000 per QALY gained, provided it was received only by patients who had exhausted their use of CYC.

This section discusses the key issues considered by the Appraisal Committee. The full list can be found in the Appraisal Committee’s FAD [63].