The Department of Health has asked the National Institute for Health and Care Excellence (NICE) to produce guidance on using rifaximin-a in the NHS in England and Wales. The Appraisal Committee has considered the evidence submitted by the manufacturer and the views of non-manufacturer consultees and commentators, and clinical specialists and patient experts.

This document has been prepared for consultation with the consultees. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the consultees and commentators for this appraisal (see section 9) and the public. This document should be read along with the evidence base (the evaluation report).

The Appraisal Committee is interested in receiving comments on the following:

• Has all of the relevant evidence been taken into account?
• Are the summaries of clinical and cost effectiveness reasonable interpretations of the evidence?
• Are the provisional recommendations sound and a suitable basis for guidance to the NHS?
• Are there any aspects of the recommendations that need particular consideration to ensure we avoid unlawful discrimination against any group of people on the grounds of race, gender, disability, religion or belief, sexual orientation, age, gender reassignment, pregnancy and maternity?

Note that this document is not NICE's final guidance on this technology. The recommendations in section 1 may change after consultation.

After consultation:

• The Appraisal Committee will meet again to consider the evidence, this appraisal consultation document and comments from the consultees.
• At that meeting, the Committee will also consider comments made by people who are not consultees.
• After considering these comments, the Committee will prepare the final appraisal determination (FAD).
• Subject to any appeal by consultees, the FAD may be used as the basis for NICE’s guidance on using rifaximin-a in the NHS in England and Wales.

For further details, see the Guides to the technology appraisal process.

The key dates for this appraisal are:

Closing date for comments: 17 July 2013 (5pm)

Second Appraisal Committee meeting: 30 July 2013

Details of membership of the Appraisal Committee are given in section 8, and a list of the sources of evidence used in the preparation of this document is given in section 9

1  Appraisal Committee’s preliminary recommendations

1.1  Rifaximin-a is not recommended within its marketing authorisation, that is, for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older.

1.2  People currently receiving rifaximin-a that is not recommended according to 1.1 should be able to continue treatment until they and their clinician consider it appropriate to stop.

2  The technology

2.1  Rifaximin-a (Targaxan, Norgine) is a semi-synthetic derivative of the antibiotic rifamycin, which inhibits ribonucleic acid (RNA). Rifaximin-a decreases intestinal production and absorption of ammonia, which is thought to be responsible for the neurocognitive symptoms of hepatic encephalopathy, thereby delaying the recurrence of acute episodes. Rifaximin-a has a UK marketing authorisation ‘for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients aged 18 years or older’. The summary of product characteristics highlights that 91% of the patients in the pivotal study were using concomitant lactulose.

2.2  The summary of product characteristics lists the following common adverse reactions for rifaximin-a: depression, dizziness, headache, dyspnoea, abdominal pain upper, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia, anaemia, oedema peripheral and pyrexia. For full details of adverse reactions and contraindications, see the summary of product characteristics.

2.3  Rifaximin-a is available as 550 mg film-coated tablets at a net price of £259.23 per 56-tablet pack (excluding VAT; ‘Medicines Index of Medicinal Specialties [MIMS]). It is administered orally at a recommended dose of 550 mg twice daily. The manufacturer estimated an average cost of £1689.65 for 6 months of treatment. Costs may vary in different settings because of negotiated procurement discounts.

3  The manufacturer’s submission

The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of rifaximin-a and a review of this submission by the Evidence Review Group (ERG; section 9).

Clinical-effectiveness evidence

3.1  The manufacturer conducted a systematic literature review and identified 3 relevant studies including rifaximin-a. Of these, 2 studies were excluded because the doses used were different from those in the UK marketing authorisation for rifaximin-a. The submission therefore included 1 study (Bass et al. 2010) which reported results from the pivotal trial – RFHE3001. This was a 6 month, international, multicentre, randomised, double-blind, placebo-controlled trial comparing rifaximin-a with placebo for maintaining remission in people with recurrent, overt, episodic hepatic encephalopathy resulting from chronic liver disease. Patients receiving lactulose at baseline were allowed to continue its use during the study period and dose changes were allowed as needed. The manufacturer also identified a second trial – RFHE3002. This was an international, multicentre, single-arm, open-label study, which assessed the long-term safety and tolerability of rifaximin-a in patients with a history of hepatic encephalopathy. It was an extension to RFHE3001 for patients who completed RFHE3001 and for new patients. The manufacturer stated that no peer reviewed publications of RFHE3002 were available at the time of the evidence submission to NICE.

RFHE3001 trial

3.2  Patients were enrolled in RFHE3001 if they had a Conn score of 0 or 1 and were in remission after 2 or more documented recurrent episodes of overt hepatic encephalopathy resulting from chronic liver disease, or portal hypertension equivalent to a Conn score of 2 or more in the 6 months before screening. The Conn score measures the severity of impaired mental status on a scale of 0–4, with higher scores indicating more severe impairment. Patient characteristics at baseline were generally similar between the 2 treatment groups. Patients were only enrolled if they had a Model End Stage Liver Disease (MELD; used to predict survival to prioritise liver transplant) score of less than 25, therefore patients with more severe liver disease (MELD score of 25 or more) were excluded from the study. After screening, 299 patients were randomised to receive either rifaximin-a 550 mg (rifaximin-a group; n=140) or matching placebo (placebo group; n=159) twice daily, plus ongoing treatment with lactulose. In the rifaximin-a and placebo groups, 91.4% and 91.2% of patients took concomitant lactulose respectively. The mean duration of treatment was 130.3 days in the rifaximin-a group and 105.7 days in the placebo group. The rate of adherence, defined as the use of at least 80% of dispensed tablets, was high in both treatment groups (84.3% in the rifaximin-a group and 84.9% in the placebo group). Patients could discontinue treatment if they had an adverse event with an unacceptable risk to them, developed any condition meeting the exclusion criteria, had a breakthrough episode of overt hepatic encephalopathy, became pregnant or asked to be withdrawn.

3.3  The primary outcome in RFHE30001 was time to first breakthrough episode of overt hepatic encephalopathy, defined as an increase in the Conn score from 0 or 1 to 2 or more or an increase in Conn and asterixis score of 1 grade each for patients who entered the study with a Conn score of 0. The asterixis score measures worsening neurological impairment in terms of flapping tremor, which is determined by the patient extending their arms with wrists flexed backwards and fingers open for 30 seconds or more. This is also measured on a scale of 0 to 4, with higher scores indicating more flapping motions. Key secondary outcomes included time to first hepatic encephalopathy-related hospital admission, time to any increase from baseline in Conn score, time to any increase from baseline in asterixis score, mean change from baseline in fatigue domain score on the Chronic Liver Disease Questionnaire (CLDQ) at end of treatment and mean change from baseline in venous ammonia concentration at end of treatment. The CLDQ was used by patients to measure their level of fatigue on a 7-point scale, with ‘1’ representing a high degree of fatigue and ‘7’ representing minimal fatigue. Results were based on the ITT population, that is, all randomised patients who received at least 1 dose of the study drug.

3.4  There was a statistically significant reduction of 58% in the risk of a breakthrough episode with rifaximin-a compared with placebo during the 6-month study period, with a hazard ratio (HR) of 0.42; 95% confidence interval [CI] 0.28 to 0.64, p<0.001. Patients who stopped early for reasons other than a breakthrough episode of overt hepatic encephalopathy were contacted 6 months after randomisation to check if they had a breakthrough episode. The manufacturer stated that therefore breakthrough episodes of overt hepatic encephalopathy were captured completely for up to 6 months after randomisation. Patients who did not have a breakthrough episode during the study period were followed-up and assessed after the study was discontinued. Their results were similar to the results for the 6-month study period, with a statistically significant reduction in the risk of a breakthrough episode with rifaximin-a compared with placebo, with a hazard ratio of 0.46; 95% CI 0.31 to 0.69, p<0.0001.

3.5  Age, MELD score, duration of current verified remission and number of prior hepatic encephalopathy episodes were identified as significant prognostic factors. To control for these factors because of chance imbalances between treatment groups, multivariate analysis was performed using the Cox proportional hazards model. This resulted in a statistically significant reduction in the risk of a breakthrough episode of overt hepatic encephalopathy with rifaximin-a compared with placebo (HR 0.40; 95% CI 0.26 to 0.62, p<0.0001).

3.6  The manufacturer carried out a sensitivity analysis of the primary outcome to exclude patients with comorbid conditions such as constipation, analgesic use, infection and portal shunt surgery. There were statistically significant risk reductions in breakthrough episodes in patients with comorbid conditions (HR 0.25; 95% CI 0.11 to 0.57, p=0.0004) and in patients without comorbid conditions (HR 0.51; 95% CI 0.31 to 0.84, p=0.0068) with rifaximin-a compared with placebo. The manufacturer also presented another sensitivity analysis that excluded patients who took concomitant medications. This also resulted in a statistically significant reduction in the risk of a breakthrough episode with rifaximin-a compared with placebo (HR 0.42; 95% CI 0.28 to 0.64, p<0.0001).

3.7  Rifaximin-a was associated with statistically significant reductions compared with placebo for the secondary outcomes of time to first hepatic encephalopathy-related hospital admission (HR 0.50; 95% CI 0.29 to 0.87, p=0.01) and time to any increase from baseline in Conn score (HR 0.46; 95% CI 0.31 to 0.69, p<0.0001). However, the reduction in time to any increase from baseline in asterixis score with rifaximin-a did not reach statistical significance when compared with placebo (HR 0.65; 95% CI 0.41 to 1.01, p=0.0523). The differences in the changes from baseline in CLDQ fatigue scores were minimal (3.28 compared with 3.34 at baseline and 3.57 compared with 3.51 at the end of treatment for the rifaximin-a and placebo groups respectively). The manufacturer stated that this was because patients were not able to complete the CLDQ assessment during a breakthrough episode because of altered mental and neuromotor status. Therefore, the CLDQ results for these patients would be similar to baseline levels because mental status was closer to baseline levels at the end of treatment assessments. The rifaximin-a group had greater reductions in venous ammonia levels compared with the placebo group, although the difference was not statistically significant (p=0.0818). The manufacturer stated that the mortality data from the trial were not mature enough to address the impact of rifaximin-a on survival.

3.8  Pre-planned subgroup analyses of the primary outcome were evaluated according to geographic region, age, sex, race or ethnic group, baseline MELD score, baseline Conn score, diabetes at baseline, duration of current verified remission, number of episodes of hepatic encephalopathy within the 6-month period before randomisation, lactulose use at baseline, and previous transjugular intrahepatic portosystemic shunt. The effect of rifaximin-a in reducing the risk of breakthrough episodes of overt hepatic encephalopathy compared with placebo during the 6-month study period was consistent across the pre-defined subgroups, although the effect was not statistically significant in the subgroup with MELD scores of 19 to 24 (26 of the 299 patients, p=0.21) and the subgroup who did not receive lactulose at baseline (26 of the 299 patients, p=0.33).

3.9  The safety population (n=299) was described by the manufacturer as patients who received at least 1 dose of study drug and provided at least 1 post-baseline safety assessment. In the rifaximin-a group, 80% of patients had adverse events during the study compared with 79.9% in the placebo group. Most adverse events were mild or moderate. The rifaximin group had higher incidences of anaemia (rifaximin compared with placebo; 7.9%: 3.8%), peripheral oedema (15%: 8.2%), pyrexia (6.4%: 3.1%), arthralgia (6.4%: 2.5%), and dizziness (12.9%: 8.2%) than the placebo group. Treatment-related adverse events occurred in 19.3% of patients in the rifaximin-a group compared with 21.4% in the placebo group. Approximately 11.4% of patients in the rifaximin-a group and 21.4% in the placebo group had breakthrough episodes of overt hepatic encephalopathy that were considered serious adverse events (for example, needing hospitalisation). A total of 10 (7.1%) patients in the rifaximin-a group and 11 (6.9%) patients in the placebo group died during the study, mainly because of conditions associated with disease progression, including hepatic cirrhosis, decompensated liver cirrhosis or hepatic failure. Adverse events leading to study discontinuation occurred in 21.4% of patients in the rifaximin-a group compared with 28.3% of patients in the placebo group. The manufacturer stated that most of the study discontinuations from adverse events were caused by hepatic encephalopathy events. Adverse events of special interest based on known potential side effects of systemic antibiotics and prior experience with rifaximin-a occurred similarly between the treatment groups, with diarrhoea being the most common (10.7% with rifaximin-a and 13.2 % with placebo).

RFHE3002 trial

3.10  A total of 322 patients were enrolled in the RFHE3002 single-arm, open label study. Of these, 152 continued from RFHE3001 (70 patients from the rifaximin-a group and 82 from the placebo group) and 170 patients were newly enrolled. All patients had a Conn score of 0 to 2 at enrolment and the newly enrolled patients had 1 or more verifiable hepatic encephalopathy episodes in the 12 months before screening. All patients received rifaximin-a 550 mg twice daily and were followed up for at least 24 months, during which time treatment was still ongoing on an outpatient basis until regulatory approval of rifaximin-a or until the sponsor closed the study, whichever came first. All concomitant drugs, including those from RFHE3001, were maintained at stable doses whenever possible. The criteria for study discontinuation were the same as those for RFHE3001, although patients who had an episode of recurrent hepatic encephalopathy during the study were not automatically withdrawn and were allowed to continue on medication.

3.11  Most patients had baseline Conn scores of either 0 (66%) or 1 (30%) and asterixis scores of 0 (71%) or 1 (24%). The time since the most recent verified hepatic encephalopathy episode was shorter in the new rifaximin-a group compared with the continuing rifaximin-a group. The 2 groups of patients were also different in terms of the number of hepatic encephalopathy episodes experienced before screening for RFHE3002 because of the differences in the number of hepatic encephalopathy episodes needed for inclusion in the 2 studies. The manufacturer indicated that the rest of the baseline characteristics were commercial in confidence.

3.12  The main efficacy outcomes assessed were change from baseline in Conn scores and asterixis scores over time. However, the manufacturer indicated that these results were commercial in confidence. The manufacturer stated that the profiles of the time to first breakthrough episode of overt hepatic encephalopathy demonstrated long-term maintenance of remission in new rifaximin‑a and continuing rifaximin-a patients. In addition, 60 rifaximin-a patients from RFHE3001 who had not had an episode of hepatic encephalopathy were followed during RFHE3002. The incidence of breakthrough episodes for these patients was lower than in the RFHE3001 placebo group, after adjusting for the different exposure time between rifaximin-a and placebo. The manufacturer also stated that the all-cause hospitalisation rate was similar to that seen for rifaximin-a during the shorter double-blind trial. However, hazard ratios were not presented.

3.13  A total of 300 patients (93.2%) reported an adverse event in RFHE3002 and approximately 56% of patients receiving rifaximin-a had severe adverse events. Overall, 67 deaths occurred during the study or within 30 days after the last dose of rifaximin-a and 8 patients died more than 30 days after their last dose. The manufacturer stated that none of these deaths were related to rifaximin-a. The manufacturer indicated that the data for treatment-related adverse events, severe adverse events and adverse events resulting in study discontinuation were commercial in confidence.

Cost-effectiveness evidence

3.14  The manufacturer conducted a systematic review of the literature and identified 1 study in its original submission, followed by 2 additional studies identified as part of the updated search conducted in response to clarification. The manufacturer, however, stated that these were not considered to be relevant because the patient population and outcomes did not match those of the current decision problem. The manufacturer stated that a comparison with neomycin was excluded because it is not routinely used in clinical practice, no clinical data are available for the use of neomycin in this indication, it is associated with risks of ototoxicity, nephrotoxicity and hepatic impairment and it is also not licensed for the indication being appraised.  

3.15  The manufacturer carried out a de novo analysis of the cost effectiveness of rifaximin-a plus concomitant lactulose compared with placebo plus concomitant lactulose, given that approximately 91% of patients in each arm of RFHE3001 received concomitant lactulose. A Markov cohort model consisting of 3 states (remission, overt and dead) was developed to reflect the clinical pathway of hepatic encephalopathy. All patients enter the model in the remission state and, in each cycle, patients can remain in remission, progress to the overt state (breakthrough and subsequent episodes that may include hospital admission), return to the remission state from the overt state or progress to the dead state from the remission or overt states. The model had a time horizon of 5 years consisting of monthly cycles, did not include a half-cycle correction, and both costs and benefits were discounted at 3.5%. The analysis was performed from the perspective of the NHS and personal social services.

3.16  Transition probabilities between the remission and overt states in the model were derived from survival functions based on time-to-event data from the ITT population in RFHE3001. A separate Kaplan-Meier plot of time to first breakthrough episode of hepatic encephalopathy was available for rifaximin-a patients who were in remission at the end of the 6-month RFHE3001 study and elected to join the RFHE3002 open label extension study. Time to first breakthrough episode of hepatic encephalopathy was extracted and combined from the Kaplan-Meier survival curves in RFHE3001 and RFHE3002 and parametric survival distributions were fitted to the combined dataset for rifaximin patients in order to extrapolate the pivotal study results beyond the final 168 days observation point in the RFHE3001 study. Data from RFHE3001 only were used for the placebo group. The survival curves were then extrapolated beyond 168 days for both groups using a log-normal distribution, which the manufacturer considered to provide the best model fit based on Akaike and Bayesian information criteria and visual inspection.

3.17  Given that time to subsequent episodes was not available from RFHE3001, the manufacturer assumed that the risk of having a subsequent breakthrough episode was independent of the risk of preceding episodes and the time spent in the remission state. It was also assumed that the risk reduction for the first breakthrough episode could also be applied to subsequent episodes, based on clinical expert opinion, and this was assumed to be constant over time for subsequent episodes. Therefore, data on time to first breakthrough episode were used to model the probability of subsequent episodes and this was extrapolated to 5 years using an exponential distribution. The hazard ratio for rifaximin-a compared with placebo was derived from the resulting parameter estimates and applied to the baseline survivor function (placebo) to estimate the survivor function for rifaximin-a.

3.18  The baseline mortality in the model was a combination of all-cause mortality and hepatic encephalopathy-specific mortality. The manufacturer estimated the risk of all-cause mortality based on the age-related life table data for England and Wales from the Office for National Statistics. This risk was adjusted for sex, based on the ratio of men to women in RFHE3001. Hepatic encephalopathy-specific mortality was estimated from other external data sources (Bustamante et al. 1999 and Shawcross et al. 2011) rather than the RFHE3001 data. The manufacturer stated that this was because the trial population did not reflect the range of patients who would present with hepatic encephalopathy in clinical practice. In addition, patients who have hepatic encephalopathy were considered to be at a higher mortality risk than patients without it and there was an increased risk of mortality associated with underlying liver disease. The manufacturer stated that data from the trial were not sufficiently mature for an analysis of mortality. The data from Bustamante et al. showed the survival curve up to 48 months for cirrhotic patients who developed hepatic encephalopathy. These data were extrapolated for 5 years using the log-normal distribution, which provided the best model fit based on Akaike and Bayesian information criteria and visual inspection. Time-dependent probabilities over 5 years were estimated using the formula in Briggs (2006). The mortality risk at each level of Conn score was based on clinical expert opinion and a publication by Shawcross et al. (2011).

3.19  The overt state also included hospital admissions caused by hepatic encephalopathy episodes. In RFHE3001, 19 of the 31 patients (61.29%) in the rifaximin-a group and 36 of the 73 patients (49.32%) in the placebo group were hospitalised because of a breakthrough episode. These 6-month probabilities of hospital admission (61.29% and 49.32%) were converted to monthly probabilities of 14.63% and 10.71% respectively (assuming a constant hazard over time) and applied to the patients predicted to reach the overt health state.

3.20  The utility values used in the model were derived from 200 randomly selected members of the general public, using the time-trade-off and standard gamble approach. Collection of these data was commissioned by the manufacturer because no appropriate generic preference-based measure of quality of life was used in RFHE3001. The manufacturer stated that the quality of life data collected using SF-36 in the trial did not appropriately capture the detriment in quality of life with hepatic encephalopathy episodes because of the difficulties in getting patients to rate their health during an overt episode. In addition, the SF-36 was completed at discrete time points despite the short duration and infrequent occurrence of hepatic encephalopathy episodes. The manufacturer also stated that data identified from the literature search were not considered to be appropriate for this analysis. Utility values ranging from 0 for death to 1 for full health were obtained for the 5 health states valued (Conn scores 0–4). Multiple regression analyses were then used to assess the relationship between the baseline variables (such as age, sex, income, preference value for their current health) associated with the preference values for each health state. The utility values used in the model (academic in confidence) were based on the mean utilities for each Conn score weighted by the proportion of patients in each Conn score category in the overt and remission states. The utility values applied in the model were adjusted to incorporate the effect of ageing in the base-case analysis. The values estimated with the time-trade-off approach were used in the base case, whereas those from the standard gamble approach were used in sensitivity analyses. A sensitivity analysis was also conducted in which the age adjustment was removed.

3.21  The average monthly cost of rifaximin-a (£281.80) used in the model was based on the recommended dosing schedule of 550 mg twice daily at a unit price of £259.23 per 56-tablet pack. Average monthly lactulose costs (£6.64 and £7.31) for the rifaximin-a and placebo groups respectively were obtained from the ‘British national formulary’ (BNF) 64 based on the mean dose of concomitant lactulose in RFHE3001 (3.14 cups for the rifaximin-a group and 3.51 cups for the placebo group). No administration costs were included in the model because rifaximin-a and lactulose are taken orally; therefore the total costs of treatment per month were £288.34 for the rifaximin-a group compared with £7.31 for the placebo group.

3.22  A cost of £110.68 for an outpatient visit for a patient in remission was based on NHS reference costs for 2011/12 and the frequency of the visits of every 3–6 months was based on expert opinion. Based on the manufacturer’s assumption of 3-monthly outpatient visits, the monthly cost of an outpatient visit in the remission state was estimated to be £36.89. It was assumed in the model that all patients with overt hepatic encephalopathy incurred the cost of an outpatient visit (£110.68). The hospital admission costs used in the model were estimated using NHS reference costs for 2011/12 and were based on the monthly average from RFHE3001 (14.63% and 10.71%, rifaximin-a and placebo) and a mean length of stay of 5 days. This resulted in a total monthly cost (outpatient visit plus hospital admission) of £359.73 and £292.96 for the overt state for the rifaximin-a and placebo groups respectively. No costs were included in the model for adverse events because there were no statistically significant differences between the adverse events reported with rifaximin-a and placebo in RFHE3001 and there was limited evidence available for disutilities associated with the adverse events. This approach was validated by the manufacturer’s clinical experts.

3.23  The base-case results of the economic analysis showed an incremental cost of £4347.50 and an incremental QALY gain of 0.1875 for rifaximin-a plus concomitant lactulose compared with placebo plus concomitant lactulose. This resulted in an incremental cost-effectiveness ratio (ICER) of £23,186 per QALY gained.

3.24  The manufacturer also compared the number of first breakthrough episodes of overt hepatic encephalopathy and the number of deaths estimated from the model at 6 months with those seen in RFHE3001. The number of first breakthrough episodes in the model was lower (rifaximin-a: 21; placebo: 56) than in the clinical trial (rifaximin-a: 31; placebo: 73). The manufacturer explained that this was because of the increased number of deaths in the model (rifaximin-a: 68; placebo: 81) compared with the clinical trial (rifaximin-a: 10; placebo: 11). This was a result of the additional mortality risks applied in the model using external data sources to reflect the range of patients who would present with hepatic encephalopathy in clinical practice.

3.25  The manufacturer performed a one-way deterministic sensitivity analysis on several model parameters using their 95% confidence intervals. The cost-effectiveness results were most sensitive to changes in the parameters used in the extrapolation of time to first breakthrough hepatic encephalopathy episode from RFHE3001, with ICERs ranging from £20,345 to £27,121 per QALY gained. Changes in length of hospital stay and percentage of patients hospitalised, frequency and cost of outpatient visits and time-trade-off utility for the Conn scores, average daily dose of lactulose, non-malignant liver disorders and liver failure disorders with and without interventions had limited impact on the ICER with results ranging from £22,858 to £23,785 per QALY gained. The manufacturer’s probabilistic sensitivity analysis indicated that rifaximin-a plus concomitant lactulose would have a 1.6% and 99.6% chance of being cost effective compared with lactulose alone, if the maximum acceptable ICERs were £20,000 and £30,000 per QALY gained respectively.

3.26  The manufacturer also explored various scenario analyses to account for the uncertainties associated with some of the assumptions in the base-case model. Alternative parametric distributions based on proportional hazards methods (exponential, Gompertz and Weibull) were used to extrapolate survival. This resulted in ICERs of £15,032, £14,311 and £28,844 per QALY gained respectively. In response to clarification, the manufacturer also presented results using the Gamma and log-logistic distributions, which were £25,752 and £23,186 per QALY gained respectively. In another scenario, the manufacturer excluded all-cause mortality from the model to account for the fact that this may have already been included in estimates of the disease-specific mortality obtained from the external sources. However, this did not result in any significant change, with an ICER of £23,012 per QALY gained.

3.27  Excluding age adjustment for utility values and using alternative data sources for estimating utility values (standard gamble approach and the study by Wong et al. 1998) also did not lead to significant changes, with ICERs of £23,186, £24,439 and £26,431 per QALY gained respectively. The manufacturer also tested the assumption that the severity of episodes in the overt state was evenly spread across Conn scores 1 to 4 (that is, 25% of patients in each Conn score) rather than the proportions from RFHE3001 used in the base-case model. As a result, the ICER decreased to £17,155 per QALY gained. When treatment adherence was based on that seen in RFHE3001 (84.3% for rifaximin-a and 84.9% for placebo) rather than the 100% compliance assumed in the base-case model, the ICER reduced to £19,599 per QALY gained. The manufacturer highlighted that the fit of the curve to the underlying clinical trial data for time to first breakthrough episode is a key driver of the cost-effectiveness results.

3.28  The manufacturer carried out 2 subgroup analyses based on lactulose use in RFHE3001. Subgroup A included patients in the rifaximin-a and placebo groups who had concomitant lactulose (91.3%) and subgroup B was made up of the patients who did not receive concomitant lactulose in the trial (8.7%). The manufacturer advised that subgroup B should be viewed with particular caution because of the small number of patients (rifaximin-a, n=12 and placebo, n=14). Both analyses resulted in higher ICERs compared with the base case; £25,785 per QALY gained for subgroup A for rifaximin-a plus lactulose compared with placebo plus lactulose and £36,254 per QALY gained for subgroup B for rifaximin-a alone compared with placebo alone.

Evidence Review Group comments

3.29  In response to clarification, the manufacturer submitted additional searches. The ERG considered these updated searches to be the main searches for this appraisal, given that they were the most up-to-date and also overlapped the first searches from the original submission. The ERG stated that it was likely that the systematic review contained all the relevant studies. The ERG identified a 6-month trial of rifaximin-a compared with neomycin reported by Miglio et al. (1997) which was not presented in the manufacturer’s submission. In its clarification response, the manufacturer stated that this trial had been identified but excluded because it was not considered appropriate for this appraisal in terms of the population, treatment regimens and outcomes included. The ERG acknowledged the manufacturer’s justification for excluding the study. However, it remained concerned about excluding neomycin from the analysis because clinical expert opinion indicated that it works by the same process as rifaximin-a and is sometimes used in clinical practice, especially for people not having a liver transplant, even though it is not as well tolerated as rifaximin-a.

3.30  The ERG stated that the evidence submitted by the manufacturer generally reflects the decision problem adequately even though the population and comparator differed from those specified in the final scope. Whereas the scope referred to adults who have had episodes of hepatic encephalopathy, the manufacturer’s submission only considered adults with chronic liver disease, excluding hepatic encephalopathy caused by acute liver disease. Patients with more severe liver disease (MELD score of 25 or more) were also excluded from the analysis. However, the ERG noted the manufacturer’s assertion that the results would apply to this population as well. The ERG was concerned about the validity of this assumption, given that the treatment effect of rifaximin-a compared with placebo was not statistically significant in the subgroup with MELD scores of 19 to 24 (the more severe MELD score category in the trial). In addition, it noted that the study by Hassest et al. (2001), which was provided as evidence for the effectiveness of rifaximin-a in patients with MELD scores of 20 or more, was a poor quality descriptive study. The final scope referred to a comparison of rifaximin-a with lactulose, neomycin or neomycin plus lactulose, but the ERG noted that the analysis presented by the manufacturer was based on rifaximin-a plus concomitant lactulose compared with placebo plus lactulose, in line with the pivotal clinical trial and UK clinical practice. The ERG stated that their clinical expert agreed that UK current practice involved using concomitant lactulose.

3.31  The ERG indicated that the quality of RFHE3001 was high. It considered that trial randomisation was carried out properly and treatment allocation was adequately concealed. It noted that the treatment groups were similar in terms of patient characteristics, although there were more men in the placebo group (67%) than in the rifaximin-a group (54%). The ERG stated that the outcomes assessed were appropriate and in line with those specified in the scope. Overall, the ERG considered the clinical effectiveness data and the statistical approaches in the manufacturer’s submission to be of good validity. However, it recognised that RFHE3002 was an unpublished study and although assessments of Conn scores and asterixis scores were conducted to monitor hepatic encephalopathy status, only summary statistics were presented for these analyses.

3.32  The ERG was satisfied with the manufacturer’s modelling approach and agreed that the health states in the model appropriately captured disease progression over time. Clinical opinion obtained by the ERG confirmed that the manufacturer’s assumption of concomitant lactulose use in both arms of the model was appropriate, but emphasised that the effectiveness results were based on 91.3% of patients using rifaximin-a with concomitant lactulose and only 8.7% taking rifaximin-a alone.

3.33  The ERG stated that a 5-year time horizon was appropriate to capture the relevant costs and benefits, but included a longer time horizon as part of an exploratory analysis, which resulted in lower ICERs (£10,482 to £19,143 per QALY gained, using different distributions). The ERG noted that approximately 10% of patients remained alive at the end of the 5-year period in the model. However, clinical expert opinion indicated that the surviving patients were likely to have stable liver disease. The ERG agreed that a half-cycle correction was not required in the model. It was noted that the manufacturer used 2 different cycle lengths in its model (28 days in some cases, such as for utility calculations and 30.4 for others). For consistency, the ERG updated the model to reflect a cycle length of 30.4 days in all cases and noted that the impact on the ICER was a minimal increase to £23,613 per QALY gained. The ERG also identified some inconsistencies in the number of patients having a hepatic encephalopathy episode, the percentages of patients in the Conn score categories used to calculate utility values, and also noted that mortality did not add up to 100%. The impact of these inconsistencies was explored in a scenario analysis in which the percentage weights attached to the Conn score categories were recalculated, so that the total population adds up to 100%. This recalculation reduced the ICER to £21,929 per QALY gained.

3.34  The ERG was satisfied with the calculation of costs in the model, although it considered that the lactulose cost should have been based on the proportion of patients who received lactulose in RFHE3001. It recalculated the cost of lactulose based on lactulose use in RFHE3001 in a scenario analysis, but the ICER remained almost the same as the base case (£23,185 compared with £23,186 per QALY gained in the base case). When this correction was considered together with the other adjustments in the model (see section 3.33), the ICER reduced to £22,298 per QALY gained. The ERG noted that the manufacturer did not include costs for adverse events because they were comparable between the rifaximin-a and placebo groups in the pivotal trial, but stated that including relative risks (or risk difference) and 95% confidence intervals for each adverse event would have strengthened this justification. However, the ERG also stated that including adverse events in the costs and QALY calculations would not have a significant impact on the ICER.

3.35  The ERG noted that the manufacturer’s choice of the log-normal distribution to extrapolate the time to the first breakthrough episode of hepatic encephalopathy was based only on the assessment of best model fit using Akaike and Bayesian information criteria and visual inspection, whereas several other steps should also have been undertaken. For example, the ERG stated that internal validity of the choice should have been assessed using log-cumulative hazard plots (which the manufacturer provided during clarification) as well as quantile–quantile plots to assess the suitability of the proportional hazards and acceleration factor (time ratio) assumptions. The ERG also stated that the expected hazard over time should have been compared with that predicted by the parametric models or used expert opinion to ensure external validity. In addition, although sensitivity analysis using alternative models was presented, the models chosen were not appropriately justified. The ERG highlighted that when other distributions were used, the final ICER varied significantly in some cases, ranging from £21,850 per QALY gained with a log-logistic distribution to £28,844 per QALY gained using a Weibull distribution. When the model adjustments discussed in sections 3.33 and 3.34 were applied by the ERG, the ICERs ranged from £13,740 per QALY gained using the Gompertz distribution to £27,825 per QALY gained using the Weibull distribution.

3.36  The ERG noted that the manufacturer used the combined dataset from RFHE3001 and RFHE3002 for the rifaximin-a arm. Data from RFHE3001 only were used for the placebo arm. The ERG stated that this approach was reasonable because it allowed all available data to be incorporated and there was no risk of bias because the population in the RFHE3002 follow-up study were patients continuing rifaximin-a from RFHE3001. However, the ERG stated that the manufacturer took the shape parameter from the regression run to fit the data for the rifaximin-a arm and used it to replace the shape parameter estimated from the log-normal distribution fitted to the placebo arm. The ERG expressed concern that this could potentially lead to incorrect estimation of effectiveness in the treatment arm, and this was supported by the sensitivity analysis conducted by the manufacturer that indicated that varying the values of the shape parameters had a considerable impact on the ICER.

3.37  The ERG explored the impact of using data from RFHE3001 only and this resulted in a higher ICER compared with the base case of £29,038 per QALY gained, although it stated that the ICER may not be correct because of a possible error in the estimate of 1 of the parameters of the log-normal regression. In response, the manufacturer indicated that correcting these values would reduce the ICER by approximately £4000 per QALY gained. In addition, the ICERs ranged from £20,102 per QALY gained using the Weibull distribution to £29,038 per QALY gained using the log-normal distribution (including the combined model adjustments in section 3.34). In addition, the ERG also conducted an analysis with a time horizon based on the duration of both trials (without extrapolating the risk of overt episodes beyond the trial duration). This resulted in an ICER of £21,424 per QALY gained. The ERG noted that the survival curves estimated using the combined dataset potentially overestimate the effect of rifaximin-a in the first 6 months, whereas the curves estimated using only the RFHE3001 data potentially underestimate the effect of rifaximin-a after the first 6 months. Based on visual inspection only, the ERG also noted that the log-normal distribution provides the best model fit to extrapolate the time to the first breakthrough episode of hepatic encephalopathy when the combined dataset was used (ICER of £22,298 per QALY gained), whereas the Gompertz distribution provides the best fit when the RFHE3001 data were used (ICER of £27,139 per QALY gained). Therefore it suggested that the ICER was likely to lie between £22,298 and £27,139 per QALY gained.

3.38  The ERG stated, based on clinical expert opinion, that the manufacturer’s assumption of a constant probability of subsequent episodes over time did not reflect reality. It stated that the impact of this assumption was not easily foreseen and highlighted that this may be a potential driver of uncertainty in the ICER estimated. It was also concerned that using an exponential distribution, which implies a constant and proportional hazard between treatment arms, did not appear to be a good fit to the data based on Akaike and Bayesian information criteria and visual inspection. The ERG considered the manufacturer’s use of external data to model hepatic encephalopathy-specific mortality to be appropriate because it captured mortality for a wider group of people with hepatic encephalopathy. It noted that the mortality assumed for Conn score categories 3 and 4 may have been overestimated and when this was reduced by 5% and 10%, the overall mortality in the overt state would decrease, resulting in higher ICERs of £23,285 and £24,412 per QALY gained respectively (that is, an approximately £1000 to £2000 increase from an ICER of £22,298 corresponding to the manufacturer’s base case ICER adjusted by the ERG). It also highlighted that the difference in mortality in the overt and remission states was a key driver of the difference in QALYs across treatment groups.

3.39  The ERG noted that although more patients had an episode of hepatic encephalopathy in the placebo arm than in the rifaximin-a arm, the rate of hospital admission for those who had an episode was higher in the rifaximin-a arm. Therefore, the overall effect of the costs of hospital admission on the ICER was neutralised to some extent, indicating that this was not a key driver of the cost-effectiveness results. Further to the manufacturer’s justification of not using the utility values collected using the SF-36 in RFHE3001 (see section 3.20), the ERG also examined the quality of life study by Sanyal et al. (2011) which reported CLDQ data from RFHE3001. It noted that the final scores on the CLDQ were not directly comparable to the standard utility scale of 0 to 1. The ERG therefore stated that the manufacturer’s approach of eliciting utility values from the general population was reasonable.

3.40  The ERG noted that the manufacturer’s subgroup analysis on the concomitant use of lactulose was not based on pre-planned subgroup analysis in RFHE3001. Nevertheless, it considered the analysis to be informative, but advised that the results should be interpreted with caution, especially because of the small sample size in subgroup B (patients who did not receive lactulose, 8.7% of the RFHE3001 population). The ERG also stated that the one-way sensitivity analysis had not been clearly presented and was concerned that some parameters were excluded, such as the exponential regression parameters used to model subsequent episodes and the log-normal constant parameter used to model time to first hepatic encephalopathy episode in the placebo arm. It performed a one-way sensitivity analysis for these parameters and the resulting ICERs ranged from £20,345 to £26,105 per QALY gained. The ERG also identified a linking mistake in the model, which had an impact on the probabilistic parameters in the log-normal distribution used to model time to first breakthrough episode in the rifaximin-a arm. Correcting this mistake suggested that the ICER estimated from the probabilistic sensitivity analysis may vary across a wider range than reported by the manufacturer (values not reported).

3.41  Full details of all the evidence are in the manufacturer’s submission and the ERG report.

4  Consideration of the evidence

The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of rifaximin-a, having considered evidence on the nature of hepatic encephalopathy and the value placed on the benefits of rifaximin-a by people with the condition, those who represent them, and clinical specialists. It also took into account the effective use of NHS resources.

4.1  The Committee considered the clinical management of maintaining remission from episodes of hepatic encephalopathy. The Committee heard from the clinical specialists that after an episode of overt hepatic encephalopathy and treatment to address the precipitating factor, it was important to prevent or reduce the recurrence of overt episodes, which may be fatal. It heard that rifaximin-a was the only licensed treatment available to maintain remission from hepatic encephalopathy episodes. The patient expert stated that hepatic encephalopathy has a profound impact on patients’ daily activities and quality of life with symptoms including personality changes, reduced levels of consciousness and altered neuromuscular activity, with a resulting impact on caregivers. The Committee heard that current standard practice included treatment with lactulose, or other laxatives, primarily because hepatic encephalopathy episodes are often triggered by constipation. However, the Committee heard that lactulose was not well tolerated; when used in large doses it can cause diarrhoea, although doses were titrated to improve their tolerability. The patient expert emphasised that this treatment is considered undignified and there is a need for alternative treatment. The patient expert also emphasised that adding rifaximin-a to current treatment with lactulose may result in reduced doses of lactulose being given and this could improve adherence to treatment. The clinical specialists also stated that neomycin was not used routinely in clinical practice because of the significant toxicity associated with its long-term use. In particular, its association with deafness made it an unacceptable alternative. The Committee recognised the need for alternative treatment options in maintaining remission from episodes of hepatic encephalopathy and also concluded that neomycin was not an appropriate comparator for this appraisal.

Clinical effectiveness

4.2  The Committee discussed the pivotal RFHE3001 trial. The Committee was satisfied that the trial was well conducted and that relevant outcomes were assessed in line with the scope of the appraisal, including health-related quality of life using the CLDQ and SF-36 questionnaire. It was aware that quality of life was also assessed in a post-hoc analysis using the CLDQ. However, the Committee noted that mortality was not reported because the data were not considered mature enough to assess mortality. The Committee noted that patients with more severe liver disease (MELD score of 25 or more) were excluded from the trial, but that the manufacturer had suggested that the trial results may apply to this group. It noted the ERG’s concerns that this was unlikely because the effectiveness in the subgroup of patients with MELD scores of 19 to 24 was not statistically significant, although the Committee recognised that this subgroup comprised only 26 of the 299 patients in RFHE3001. However, the Committee heard from the clinical specialists that, in practice, patients with a MELD score greater than 24 have a poor prognosis and are often hospitalised awaiting liver transplant. The clinical specialists stated that rifaximin-a would not generally be prescribed for these patients because it was unlikely to provide any meaningful benefit. The Committee was aware that 91.4% of patients in the rifaximin-a arm and 91.2% of patients in the placebo arm received concomitant lactulose and queried whether this reflects normal practice. The clinical specialists confirmed that this was in line with UK clinical practice and there was limited evidence on the efficacy of rifaximin-a monotherapy (8.6% of patients in RFHE3001).The Committee concluded that RFHE3001 was appropriately conducted and relevant to UK clinical practice.

4.3  The Committee examined the clinical-effectiveness data from RFHE3001,which compared rifaximin-a with placebo. It was aware that the efficacy of rifaximin-a was based on approximately 91% of the patients in each arm receiving concomitant lactulose. The Committee noted that there was a statistically significant increase in time to first breakthrough episode of overt hepatic encephalopathy compared with placebo (HR 0.42; 95% CI 0.28 to 0.64, p<0.001) for the ITT population. It also noted that rifaximin-a was associated with statistically significant reductions in hepatic encephalopathy-related hospital admissions and time to any increase from baseline in Conn scores. However, the improvements in asterixis score and venous ammonia levels were not statistically significant, and the difference in changes in CLDQ fatigue scores between the rifaximin-a arm and placebo arm was minimal. The Committee also heard from the clinical specialists that apart from reducing blood ammonia levels, rifaximin-a also influenced endotoxin production and reduced systemic inflammation, which plays an important role in the development of hepatic encephalopathy. The Committee questioned whether this was in line with the proposed mode of action of rifaximin-a, but the manufacturer explained that the pathogenesis remains speculative and is an area of ongoing research. The clinical specialists stated that both the ammonia-lowering and endotoxin-lowering properties of rifaximin-awere relevant in producing a treatment effect. The Committee also discussed RFHE3002, which was performed as an open label, follow-up study to assess the long-term safety and tolerability of rifaximin-a. It noted that not all patients from RFHE3001 continued in RFHE3002, which may be a potential source of selection bias. RFHE3002 provided only exploratory effectiveness data. The Committee also recognised that RFHE3002 was unpublished, although it considered it to be informative to some extent. The Committee considered the pivotal RFHE3001 trial to be the main source of evidence for determining the clinical efficacy of rifaximin-a, and concluded that rifaximin-a was effective in maintaining remission from episodes of hepatic encephalopathy in the trial population.

4.4  The Committee considered the adverse event profile associated with rifaximin-a in RFHE3001. It noted that hepatic encephalopathy adverse events leading to study discontinuation occurred less frequently in the rifaximin-a group than in the placebo group. However, anaemia, peripheral oedema, pyrexia, arthralgia and dizziness occurred more frequently in the rifaximin-a group than in the placebo group (see section 3.9). The Committee noted that approximately 56% of patients had severe adverse events in RFHE3002. The Committee also noted from the UK public assessment report that cases of Clostridium difficile associated diarrhoea have been reported with the use of rifaximin-a. It understood that this was a potential ongoing safety concern with the use of antibacterial agents including rifaximin-a. It heard from the manufacturer that the UK public assessment report stated that there were no new safety concerns with rifaximin-a and the benefit-risk profile was considered to be positive because therapeutic value has been demonstrated. It noted the patient expert’s statement that the potential side effects of rifaximin-a were considered to be more tolerable than the physical and psychological side effects associated with current treatment (such as diarrhoea associated with lactulose treatment), which have a detrimental effect on quality of life for patients and carers. The Committee concluded that the current evidence indicates that rifaximin-a has an acceptable adverse event profile.

 Cost effectiveness

4.5  The Committee considered the manufacturer’s economic model and the ERG’s critique of the model. It accepted the exclusion of neomycin from the analysis because it was not routinely used in clinical practice. It considered the 5-year time horizon to be appropriate because there was no robust evidence of a mortality effect; otherwise a life time horizon would be more appropriate. The Committee discussed the assumptions used to model subsequent hepatic encephalopathy episodes. It was concerned about the plausibility of the manufacturer’s assumption of a constant hazard for hepatic encephalopathy events. It heard from the clinical specialists that a previous hepatic encephalopathy episode would increase the likelihood of subsequent episodes and the risk of mortality would be higher with each additional episode. The Committee considered that more health states should have been included in the model to capture the complexities around the recurrence of subsequent hepatic encephalopathy episodes. The Committee concluded that the model structure oversimplified the nature and course of the disease.

4.6  The Committee discussed the use of the combined dataset from RFHE3001 and RFHE3002 to model the rifaximin-a arm. It was aware that the primary objective of RFHE3002 was to determine the long-term safety and tolerability of rifaximin-a. The Committee did not consider combining datasets to be appropriate because it broke randomisation and introduced bias, given that RFHE3002 did not include all the patients from RFHE3001. Moreover, only data from RFHE3001 were used to model the placebo arm. The Committee noted that, despite this, distributions to extrapolate effectiveness data beyond the duration of the trial were chosen based on the combined dataset for both rifaximin-a and placebo arms. It noted that a log-normal distribution was fitted to the placebo arm of RFHE3001 and that the shape parameter from this regression was replaced by the shape parameter from the regression for the rifaximin-a arm. It noted the substantial difference between the ICERs generated with the exponential and Weibull curves using the combined dataset (approximately £14,000 and £28,000 per QALY gained respectively, including the ERG adjustments). However, when the RFHE3001 data were used alone, the difference in the ICERs based on the 2 distributions was minimal as expected (£20,230 and £20,102 per QALY gained for the exponential and Weibull curves respectively), which further highlighted the uncertainties surrounding the use of the combined dataset. The Committee therefore concluded that only the RFHE3001 data should have been used to model both treatment arms.

4.7  The Committee considered the utilities applied by the manufacturer in the economic model. It noted that the utilities used were derived from the general public in a study commissioned by the manufacturer. The Committee noted the manufacturer’s justification that quality of life data collected from RFHE3001 using the CLDQ and SF-36 were collected at discrete time points and did not reflect the detriment in quality of life of hepatic encephalopathy episodes because patients were unable to rate their health during an overt episode; therefore the data collected only reflected the remission period. However, the Committee was aware that the SF‑36 included a recall period and could potentially capture some of the impact of an overt episode. The manufacturer stated that the patients who had an overt episode had to discontinue the study and were hospitalised, and their recall was not very good. The Committee was concerned that the utilities estimated from the general public may not be reliable. In particular, the Committee noted that the description used in the time trade-off approach was negatively worded and also included the probability of mortality, which could skew the results. It also considered that the final utility estimates used in the model were too high, especially for people with underlying liver disease. The Committee concluded that it would be more appropriate to incorporate the quality of life data collected from RFHE3001 in the model and any external data should only be used to supplement and validate this.

4.8  The Committee considered the costs used in the model. It was aware that, based on the literature, length of hospital stay was assumed to be equal in both treatment arms. The Committee considered it would have been useful for this information to have been collected in the trial so that differences in length of stay could have been appropriately captured in the model. It noted that adverse events were excluded from the cost calculation on the basis that there were no statistically significant differences between the treatment arms in RFHE3001 and there was limited evidence for disutilities associated with the adverse events. It heard from the clinical specialists that adverse events were minimal and primarily related to lactulose use. The ERG stated that including adverse events was not likely to have a large impact on the cost-effectiveness results. The Committee concluded that rifaximin-a had an acceptable adverse event profile; however it was uncertain of the impact on the ICER and considered that an attempt should have been made to capture some of the differences in the costs of adverse events between the rifaximin-a and placebo arms.

4.9  The Committee considered the plausibility of the mortality estimated from the model. It noted that approximately 50% of the model population died over a 6-month period compared with 7% (21 deaths) in RFHE3001. It noted the manufacturer’s statement that this was a result of the external data used to model the risk of mortality. The clinical specialists stated that mortality in the model was much higher than would be seen in clinical practice and that the mortality in the trial population would more closely reflect observed mortality. They suggested that the low numbers in RFHE3001 could be a result of these patients having liver transplant. However, the Committee noted that only 1 patient from the trial (the placebo arm) had a liver transplant. The Committee was also concerned that the model predicted a 5% reduction in the risk of mortality with rifaximin-a compared with placebo during the first 6 months of the model and over the 5-year time horizon when there were no differences between the groups in RFHE3001. It also noted that most of the benefits in the model accrued from extended survival rather than improved quality of life, indicating that the survival benefit with rifaximin-a was a major driver of the cost-effectivenessresults. The clinical specialists suggested that a mortality risk reduction of 5% could be possible between treatment arms, although they acknowledged that there was no definitive evidence in the literature demonstrating a mortality benefit. The Committee noted that no differential mortality benefits between the treatment arms were apparent in the trial, and recognised that RHFE3001 was of short duration and that the manufacturer regarded the mortality data as being immature. The Committee noted the exploratory analyses reducing mortality conducted by the ERG,but noted that these were adjusted for both arms, without any variation in differential mortality. The Committee therefore concluded that the mortality estimates driving the results from the model were not robust.

4.10  The Committee discussed the subgroup analysis performed by the manufacturer, that is, the subgroup who received concomitant lactulose in RFHE3001 (91.3% of patients) and those who did not receive concomitant lactulose (8.7%). The Committee was concerned that the ICERs for the 2 subgroups were higher than the base-case ICER for the whole trial population, given that the 2 groups make up the trial population. The manufacturer confirmed that this was because only the RFHE3001 data were used to model the subgroups rather than the combined dataset used in the base case. The Committee notedthat the ICERs using the RFHE3001 data only were higher than those using the combined dataset. The Committee agreed with the manufacturer and the ERG that the subgroup analysis should be interpreted with caution, given the small numbers in the subgroup who did not receiveconcomitant lactulose.

4.11  The Committee considered whether rifaximin-a reflected a cost-effective use of NHS resources. The Committee noted that the manufacturer’s base-case ICER was £23,000 per QALY gained for rifaximin-a plus lactulose compared with placebo plus lactulose. It was aware that minor corrections made by the ERG resulted in an ICER of £22,000 per QALY gained. However, the Committee did not consider this ICER to be plausible based on the uncertainties associated with some of the model assumptions (see section 4.5), the use of the combined dataset to fit the model (see section 4.6), and uncertainties around the estimates of utilities (see section 4.7) and mortality (see section 4.9) in the model. It considered the RFHE3001 data more appropriate to populate the model rather than the combined dataset and noted that based on the ERG’s exploratory analysis, the Gompertz distribution provided the best model fit with the RFHE3001 data. This resulted in an ICER of approximately £27,000 per QALY gained (including the ERG’s adjustments). The Committee noted, based on exploratory analyses conducted by the ERG, that reducing the overall mortality for grade 3 and 4 Conn scores in both arms would increase the ICER by approximately £2000 per QALY gained. The Committee noted that the differential mortality benefit attributed to rifaximin-a was a major contributor to the QALY gain and considered that the ICER would be greater than £30,000 per QALY gained if no differential survival benefit accrued with rifaximin-a. Although the Committee heard from the clinical specialists that a mortality benefit with rifaximin-a may be plausible, it was presented with no evidence to support this. The Committee considered that the mortality benefit in the model was too high and was not based on the pivotal trial. After considering all the evidence, the Committee concluded that rifaximin-a could not be considered a cost-effective use of NHS resources.

4.12  The Committee noted the manufacturer’s comment regarding the innovative nature of rifaximin-a. The manufacturer stated that rifaximin-a was expected to offer a step change in the management of hepatic encephalopathy by significantly reducing breakthrough episodes and hospital admissions, while maintaining health-related quality of life. The manufacturer also highlighted the study by Bajaj et al. (2011) which shows that reducing the recurrence of hepatic encephalopathy episodes would likely have an impact on the health and quality of life of carers. The Committee heard from the clinical specialists that the use of rifaximin-a could potentially reduce the number of people on the liver transplant list, which would reduce the burden of expensive procedures on the healthcare system. The patient expert also emphasised that availability of rifaximin-a would reduce the doses of lactulose given to people, thereby improving their wellbeing. The Committee noted that rifaximin-a for treating hepatic encephalopathy was a new indication for the antibiotic and it is well tolerated, but considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Therefore, the Committee concluded that the innovative aspects of rifaximin-a were already incorporated in the economic analyses.

Summary of Appraisal Committee’s key conclusions

TAXXX	Appraisal title: Rifaximin-a for maintaining remission from episodes of hepatic encephalopathy		Section
Key conclusion
Rifaximin-a is not recommended within its marketing authorisation, that is, for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older. After considering all the evidence, the Committee concluded that rifaximin-a was effective in maintaining remission from episodes of hepatic encephalopathy in the trial population; however, given the uncertainties around the ICER, it could not be considered a cost-effective use of NHS resources.			1.1 4.3, 4.11
Current practice
Clinical need of patients, including the availability of alternative treatments		The clinical specialists stated that after an episode of overt hepatic encephalopathy and treatment to address the precipitating factor, it was important to prevent or reduce the recurrence of overt episodes, which may be fatal. The Committee heard that lactulose, which is standard treatment, was not well tolerated when used in large doses because it can cause diarrhoea and that neomycin was not used routinely in clinical practice because of the significant toxicity associated with its long-term use. The Committee recognised the need for alternative treatment options in maintaining remission from episodes of hepatic encephalopathy and also concluded that neomycin was not an appropriate comparator for this appraisal.	4.1
The technology
Proposed benefits of the technology How innovative is the technology in its potential to make a significant and substantial impact on health-related benefits?		The Committee understood that rifaximin-a was expected to reduce breakthrough episodes and hospital admissions, while maintaining health-related quality of life, but considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations.	4.12
What is the position of the treatment in the pathway of care for the condition?		Rifaximin-a has a UK marketing authorisation ‘for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients aged 18 years or older’. The Committee heard that current standard practice included treatment with lactulose, or other laxatives and that neomycin was not an appropriate comparator.	2.1 4.1
Adverse reactions		The Committee concluded that the current evidence indicates that rifaximin-a has an acceptable adverse event profile.	4.4
Evidence for clinical effectiveness
Availability, nature and quality of evidence		The Committee was satisfied that the RFHE3001 trial was well conducted and that relevant outcomes were assessed in line with the scope of the appraisal, including health-related quality of life using the CLDQ and SF-36 questionnaire. The Committee noted that the open label, follow-up study, RFHE3002, provided only exploratory effectiveness data. The Committee also recognised that RFHE3002 was unpublished, although it considered it to be informative to some extent.	4.2 4.3
Relevance to general clinical practice in the NHS		The Committee heard that patients with a MELD score greater than 24 (who were excluded from the trial) have a poor prognosis; and in practice would not generally be prescribed rifaximin-a because it was unlikely to provide any meaningful benefit. The Committee also heard that the concomitant use of lactulose by 91.3% of patients in the trial was in line with UK clinical practice and concluded that RFHE3001 was relevant to UK clinical practice.	4.2
Uncertainties generated by the evidence		The Committee noted that not all patients from RFHE3001 continued in RFHE3002, which may be a potential source of selection bias. RFHE3002 provided only exploratory effectiveness data.	4.3
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?		None	–
Estimate of the size of the clinical effectiveness including strength of supporting evidence		The Committee noted that there was a statistically significant increase in time to first breakthrough episode of overt hepatic encephalopathy compared with placebo (HR 0.42; 95% CI 0.28 to 0.64, p<0.001). It also noted that rifaximin-a was associated with statistically significant reductions in hepatic encephalopathy-related hospital admissions and time to any increase from baseline in Conn scores. However, the improvements in asterixis score and venous ammonia levels were not statistically significant, and the difference in changes in CLDQ fatigue scores between the rifaximin-a arm and placebo arm was minimal. The Committee concluded that rifaximin-a was effective in maintaining remission from episodes of hepatic encephalopathy in the trial population.	4.3
Evidence for cost effectiveness
Availability and nature of evidence		A Markov cohort model consisting of 3 states (remission, overt and dead) was developed to reflect the clinical pathway of hepatic encephalopathy. The model assessed the cost-effectiveness of rifaximin-a plus concomitant lactulose compared with placebo plus concomitant lactulose, given that approximately 91% of patients in each arm of RFHE3001 received concomitant lactulose.	3.15
Uncertainties around and plausibility of assumptions and inputs in the economic model		The Committee was concerned about the plausibility of the manufacturer’s assumption of a constant hazard for hepatic encephalopathy events. It concluded that the model structure oversimplified the nature and course of the disease. The Committee did not consider combining datasets to be appropriate because it broke randomisation and introduced bias, given that RFHE3002 did not include all the patients from RFHE3001. Moreover, only data from RFHE3001 were used to model the placebo arm. The Committee therefore concluded that only the RFHE3001 data should have been used to model both treatment arms. The Committee was concerned that the utilities estimated from the general public may not be reliable and were too high for people with underlying liver disease. The Committee concluded that it would be more appropriate to incorporate the quality of life data collected from RFHE3001 in the model and any external data should only be used to supplement and validate this. The Committee noted that approximately 50% of the model population died over a 6-month period compared with 7% (21 deaths) in RFHE3001.The Committee was also concerned that the model predicted a 5% reduction in the risk of mortality with rifaximin-a compared with placebo during the first 6 months of the model and over the 5-year time horizon when there were no differences between the groups in RFHE3001. The Committee therefore concluded that the mortality estimates driving the results from the model were not robust.	4.5 4.6 4.7 4.9
Incorporation of health-related quality-of-life benefits and utility values Have any potential significant and substantial health-related benefits been identified that were not included in the economic model, and how have they been considered?		The Committee considered that there were no additional gains in health-related quality of life over those already included in the QALY calculations. Therefore, the Committee concluded that the innovative aspects of rifaximin-a were already incorporated in the economic analyses.	4.12
Are there specific groups of people for whom the technology is particularly cost effective?		None identified.	–
What are the key drivers of cost effectiveness?		The Committee noted that most of the benefits in the model accrued from extended survival rather than improved quality of life, indicating that the survival benefit with rifaximin-a was a major driver of the cost-effectiveness results.	4.9
Most likely cost-effectiveness estimate (given as an ICER)		The Committee noted that the differential mortality benefit attributed to rifaximin-a was a major contributor to the QALY gain and that the ICER would be substantially greater than £30,000 per QALY gained if no differential survival benefit accrued with rifaximin-a.	4.11
Additional factors taken into account
Patient access schemes (PPRS)		None	–
End-of-life considerations		N/A	–
Equalities considerations and social value judgements		No potential equality issues were identified.	–

 

5  Implementation

5.1  NICE has developed tools [link to www.nice.org.uk/guidance/TAXXX] to help organisations put this guidance into practice (listed below). [NICE to amend list as needed at time of publication]

• Slides highlighting key messages for local discussion.
• Costing template and report to estimate the national and local savings and costs associated with implementation.
• Implementation advice on how to put the guidance into practice and national initiatives that support this locally.
• A costing statement explaining the resource impact of this guidance.
• Audit support for monitoring local practice.

6  Related NICE guidance

There is no related guidance for this technology.

7  Proposed date for review of guidance

7.1  NICE proposes that the guidance on this technology is considered for review by the Guidance Executive in October 2016. NICE welcomes comment on this proposed date. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.

Gary McVeigh
Chair, Appraisal Committee
June 2013

8  Appraisal Committee members and NICE project team

8.1  Appraisal Committee members

The Appraisal Committees are standing advisory committees of NICE. Members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. There are 4 Appraisal Committees, each with a chair and vice chair. Each Appraisal Committee meets once a month, except in December when there are no meetings. Each Committee considers its own list of technologies, and ongoing topics are not moved between Committees.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Professor Gary McVeigh (Chair)
Professor of Cardiovascular Medicine, Queens University Belfast and Consultant Physician, Belfast City Hospital

Professor Jonathan Michaels (Vice Chair)
Professor of Clinical Decision Science, University of Sheffield

Dr Aomesh Bhatt
Regulatory and Medical Affairs Director Europe and North America, Reckitt Benckiser

Dr Matthew Bradley
Therapy Area Leader, Global Health Outcomes, GlaxoSmithKline

Dr Ian Davidson
Lecturer in Rehabilitation, University of Manchester

John Dervan
Lay Member

Christopher Earl
Surgical Care Practitioner, Wessex Neurological Centre at Southampton University Hospital

Gillian Ells
Prescribing Advisor – Commissioning, NHS Hastings and Rother and NHS East Sussex Downs and Weald

Professor Paula Ghaneh
Professor and Honorary Consultant Surgeon, University of Liverpool

Dr Susan Griffin
Research Fellow, Centre for Health Economics, University of York

Professor Carol Haigh
Professor in Nursing, Manchester Metropolitan University

Professor John Henderson
Professor of Paediatric Respiratory Medicine, University of Bristol and Bristol Royal Hospital for Children

Dr Paul Hepple
General Practitioner, Muirhouse Medical Group

Professor John Hutton
Professor of Health Economics, University of York

Professor Peter Jones
Emeritus Professor of Statistics, Keele University

Professor Steven Julious
Professor of Medical Statistics, University of Sheffield

Dr Tim Kinnaird
Lead Interventional Cardiologist, University Hospital of Wales, Cardiff

Warren Linley
Senior Research Fellow, Centre for Health Economics and Medicines Evaluation, Bangor University

Dr John Radford
Director of Public Health, Rotherham Primary Care Trust and MBC

Dr Brian Shine
Consultant Chemical Pathologist, John Radcliffe Hospital, Oxford

Dr Murray Smith
Associate Professor in Social Research in Medicines and Health, University of Nottingham

Paddy Storrie
Lay Member

Charles Waddicor
Chief Executive, NHS Berkshire West

8.2  NICE project team

Each technology appraisal is assigned to a team consisting of 1 or more health technology analysts (who act as technical leads for the appraisal), a technical adviser and a project manager.

Nwamaka Umeweni
Technical Lead

Raisa Sidhu
Technical Adviser

Kate Moore
Project Manager

9  Sources of evidence considered by the Committee

A. The Evidence Review Group (ERG) report for this appraisal was prepared by Peninsula Technology Assessment Group (PenTAG):

• Bacelar M, et al. The clinical and cost-effectiveness of rifaximin for maintaining remission from episodes of hepatic encephalopathy: A critique of the submission from Norgine, April 2013

B. The following organisations accepted the invitation to participate in this appraisal as consultees and commentators. They were invited to comment on the draft scope, the ERG report and the appraisal consultation document (ACD). Organisations listed in I were also invited to make written submissions. Organisations listed in II and III had the opportunity to give their expert views. Organisations listed in I, II and III also have the opportunity to appeal against the final appraisal determination.

I. Manufacturer/sponsor:

• Norgine

II. Professional/specialist and patient/carer groups:

• British Liver Trust
• British Infection Association
• British Society of Gastroenterology
• Royal College of Nursing
• Royal College of Pathologists
• Royal College of Physicians

III. Other consultees:

• Department of Health
• South Essex PCT Cluster
• Welsh Government

IV. Commentator organisations (did not provide written evidence and without the right of appeal):

• Commissioning Support Appraisals Service
• Department of Health, Social Services and Public Safety for Northern Ireland
• Healthcare Improvement Scotland
• Foundation for Liver Research
• National Institute for Health Research Health Technology Assessment programme
• Peninsula Technology Assessment Group (PenTAG)

C. The following individuals were selected from clinical specialist and patient expert nominations from the consultees and commentators. They gave their expert personal view on rifaximin-αby attending the initial Committee discussion and providing written evidence to the Committee. They are invited to comment on the ACD.

• Dr Sulleman Moreea, consultant Gastroenterologist/Hepatologist, nominated by the British Society of Gastroenterology – clinical specialist
• Dr Debbie Shawcross, Senior Lecturer and Honorary Consultant in Hepatology, nominated by Norgine – clinical specialist
• Andrew Langford, Chief Executive of the British Liver Trust, nominated by British Liver – patient expert

E. Representatives from the following manufacturer/sponsor attended Committee meetings. They contributed only when asked by the Committee chair to clarify specific issues and comment on factual accuracy.

• Norgine