OBJECTIVES:To conduct an economic evaluation of levofloxacin inhalation solution (LIS) compared to aztreonam lysine inhalation solution (AZLI) in Belgium for the treatment of chronic Pseudomonas aeruginosa lung infection in adult cystic fibrosis (CF) patients.

METHODS:A 24-week cycle Markov model was developed based on the approach followed by Tappenden et al.(1) to estimate the expected costs and quality-adjusted life year (QALY) gains over three- and five-years. Utility values were dependent on lung function, exacerbations and having received lung transplantation. Model structure and transitions between the different health states of the model are presented in Figure 1.

FEV1: Forced expiratory volume in 1 second

Figure 1. Model structure

The model simulated the disease progression of CF patients as measured by the decrease in FEV1 percent predicted. Additionally, a possibility of undergoing lung transplant and mortality were integrated in the model.

The simulation started on initiation of treatment with either LIS or the comparator (AZLI). At baseline, patients were distributed across 3 levels of severity of FEV1: FEV1≥70%, FEV1 40-69% and FEV1<40%. After a treatment cycle, patients might stay at the same FEV1 state, improve, and thus transition to a lower severity state, or worsen. Patients in the FEV1<40% state might undergo lung transplantation and move to the transplantation state before entering the “Post-transplant state”. The model accounted for the fact that patients might experience exacerbations (minor and major) that had a direct impact on costs and health-related quality of life. The mortality risk depended on patient age and increased mortality was considered for patients in the “Transplantation” state. The impact of the association between mortality and FEV1% predicted was studied in a sensitivity analysis.

FEV1 percent predicted was chosen as it is a relevant surrogate outcome of the changes in lung function, but also this measure was a primary outcome in the MPEX-209 trial (2). For each FEV1 severity level, a quality of life value was assigned. Exacerbation rates were determined from the MPEX-209 trial (2) and the NMA (3) and were considered to be dependant of FEV1 and treatment. The probability of experiencing a major exacerbation was also extracted from the MPEX-209 trial (2) and was assumed to be independent of FEV1 and treatment.

Cost of AZLI was calculated based on the drug prices derived from INAMI/RIZIV base of reimbursement list of drugs and drug dosages (4). Given the similarities in the clinical trial design and study population (pre-exposed to tobramycin) the same price was assumed for LIS and AZLI, in spite of the restricted indication for LIS (adult CF patients only).

All input parameters are presented in Table 1.

Table 1. Input parameters

Base case SourceBaseline characteristicsAverage age 28 MPEX-209 (2)Patient distribution at baseline% of patients FEV1 ≥ 70% 22%

MPEX-209 (2)% of patients FEV1 40–69% 54%% of patients FEV1 < 40% 24%MortalityFEV1 health statesWeibull log lambda FEV1 -12.33

Tappenden et al. (1)Weibull gamma FEV1 3.34Post-transplantWeibull log lambda post-transplant -12.33

Tappenden et al. (1)Weibull gamma post-transplant 3.34Association between FEV1 and mortalityHR for mortality 1 Transplantation mortality0-6 months post-transplant mortality 0.103

Whiting et al. (5)6-12 months post-transplant mortality 0.103Clinical inputsTransition probabilitiesLISFEV1 ≥ 70% to FEV1 40–69% 0.129

Bayesian calibrationFEV1 40–69% to FEV1 ≥ 70% 0.069FEV1 40–69% to FEV1 < 40% 0.018FEV1 < 40% to FEV1 40–69% 0.143AZLIFEV1 ≥ 70% to FEV1 40–69% TIS 0.417

Bayesian calibrationFEV1 40–69% to FEV1 ≥ 70% TIS 0.013FEV1 40–69% to FEV1 < 40% TIS 0.081FEV1 < 40% to FEV1 40–69% TIS 0.033ExacerbationsExacerbation probability LISFEV1 ≥ 70% exacerbation probability 0.527 MPEX-209 (2)FEV1 40–69% exacerbation probability 0.685 MPEX-209 (2)FEV1 < 40% exacerbation probability 0.696 MPEX-209 (2)Proportion of major LISFEV1 ≥ 70% proportion of major 0.013

MPEX-209 (2)FEV1 40–69% proportion of major 0.013FEV1 < 40% proportion of major 0.013Exacerbation probability AZLIOR vs. LIS 0.763 NMA (3)Proportion of major AZLI FEV1 ≥ 70% proportion of major 0.013

MPEX-209 (2)FEV1 40–69% proportion of major 0.013FEV1 < 40% proportion of major 0.013UtilitiesHealth states utilitiesFEV1 ≥ 70% utility 0.74

Acaster et al. (6)FEV1 40–69% utility 0.7FEV1 < 40% utility 0.540-6 months transplantation utility 0.75

Whiting et al. (5)6-12 months transplantation utility 0.82Post-transplant utility 0.82Exacerbation utility decrementMinor exacerbation utility decrement 0.06

Bradley et al. (7)Major exacerbation utility decrement 0.25CostsCF costsFEV1 ≥ 70% CF costs € 4,594.84

KCE 2010 (8)FEV1 40–69% CF costs € 4,594.84FEV1 < 40% CF costs € 4,594.84Post-transplant follow up costs0-6 months post-transplant € 14,171.21

Whiting 2014 (5)6-12 months post-transplant € 14,171.21> 12 months post-transplant € 6,388.62

Cost-effectiveness of Levofloxacin InhalationSolution vs. Aztreonam Inhalation Solutionin Cystic fibrosis patients in Belgium G. Medic1; M. Westen1; M. Wille1; M. Hemels1

1 Raptor Pharmaceuticals, Naritaweg 165; 1043BW Amsterdam; The Netherlands

Base case SourceExacerbation costsMinor exacerbation costs € 44.47 Expert opinionMajor exacerbation costs € 7,836.96 Belgian average cost CF hospitali-

sations (9) Transplantation costsCost of transplant € 72,125.80 Belgian average cost heart and/

or lung transplantation (APR-DRG=002, anno 2013) (10)

OtherTransplantationProbability of transplantation 0.009 Tappenden 2014. (1)Exacerbation durationMinor exacerbation duration (weeks) 10 Assumption based on Bradley et

al. (7)Major exacerbation duration (weeks) 10Discount ratesCost outcomes discount 3%

Efficacy outcomes discount 3%

CF: Cystic fibrosis, FEV1: Forced expiratory volume in 1 second, LIS: Levofloxacin inhalation solution; OR: Odds ratio, AZLI: Aztreonam lysine inhalation solution, HR: Hazard ratio

The following analyses were conducted:The base case analysis was conducted from the Belgian health care perspective at 3 years and sensitivity analysis at 5-years.

Several scenario analyses were also conducted to specifically explore the uncertainty surrounding several parameters:• Scenario 1: Alternative source for utilities (1). Alternative utility estimates from

Tappenden et al. (1) were used for the following health states: FEV1 ≥ 70% predicted, FEV1 40–69% predicted, FEV1 < 40% predicted

• Scenario 2: Alternative discount rates– Scenario 2.1:

discount rate costs = 0%/ discount rate health outcomes = 0%– Scenario 2.2:

discount rate costs = 3%/ discount rate health outcomes = 3%– Scenario 2.3:

discount rate costs = 5%/ discount rate health outcomes = 5%.

Model assumptions and limitations are summarised in Table 2.

A one-way sensitivity analysis was conducted in order to identify model parameters having the greatest impact on the results. The results are presented in form of tornado chart showing the difference in the analysed outcome comparing with the base case. Only ten parameters having the greatest impact on the model results were reported on the tornado chart (Figure 2). FEV1 % predicted CF costs <40% and ≥70% are the two input parameters with the greatest impact on the incremental costs.

Figure 2. Tornado chart; LIS vs. AZLI; Three-year time horizon – Incremental costsFEV1: Forced expiratory volume in 1 second, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution, CF: Cystic fibrosis, OR: Odds ratio, HR: Hazard ratio

The results of the probabilistic sensitivity analyses are illustrated by the cost- effectiveness plane (Figure 3) and the cost-effectiveness acceptability curve (Figure 4). The probability of an incremental cost-effectiveness ratio (ICER) being less than €50,000 was 89.5%.

Figure 3. Results of the PSA LIS vs. AZLI; Three-year time horizon – Incremental Cost-Effectiveness PlanePSA: Probabilistic sensitivity analysis, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution

Figure 4. Results of the PSA LIS vs. AZLI; Three-year time horizon – Cost- Effectiveness Acceptability CurvePSA: Probabilistic sensitivity analysis, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution

In addition to the base case analysis, two scenarios were conducted to assess the impact of parameter uncertainty on the model results. In all scenarios, conclusions are similar to the base case analysis: LIS was associated with a QALY gain and was cost-saving compared to AZLI. In general, the sensitivity analyses showed that the ICER was mainly sensitive to the costs of CF management and the mortality.

CONCLUSIONS:• This model simulated the disease progression of CF patients as measured

by the decrease in FEV1 percent predicted.

• The sensitivity analyses showed that the ICER was mainly sensitive to the costs of CF management and the mortality.

• The base case results showed that the cost-effectiveness analysis of LIS is a dominant treatment option vs. AZLI over three- and five-year time horizons from the Belgian healthcare perspective.

REFERENCES1. Tappenden P, Harnan S, Uttley L, Mildred M, Walshaw M, Taylor C, et al. The cost effectiveness of dry powder antibiotics

for the treatment of pseudomonas aeruginosa in patients with cystic fibrosis. PharmacoEconomics. 2014;32(2):February.2. Stuart Elborn J, Geller DE, Conrad D, Aaron SD, Smyth AR, Fischer R, et al. A phase 3, open-label, randomized trial to

evaluate the safety and efficacy of levofloxacin inhalation solution (APT-1026) versus tobramycin inhalation solution in stable cystic fibrosis patients. J Cyst Fibros. 2015;14(4).

3. Stuart Elborn J, Vataire AL, Fukushima A, Aballea S, Khemiri A, Moore C, et al. Comparison of Inhaled Antibiotics for the Treatment of Chronic Pseudomonas aeruginosa Lung Infection in Patients With Cystic Fibrosis: Systematic Literature Review and Network Meta-Analysis. Clin Ther. 2016.

4. http://www.inami.fgov.be/fr/themes/cout-remboursement/par-mutualite/medicament-produits-sante/remboursement/specialites/Pages/specialites-pharmaceutiques-remboursables-listes-fichiers-reference.aspx#.Vy0EMY9OIy8 [Accessed 6 May 2016].

5. Whiting P, Al M, Burgers L, Westwood M, Ryder S, Hoogendoorn M, et al. Ivacaftor for the treatment of patients with cystic fibrosis and the G551D mutation: A systematic review and cost-effectiveness analysis. Health Technology Assessment. 2014;18(18):March.

6. Acaster S, Pinder B, Mukuria C, Copans A. Mapping the EQ-5D index from the cystic fibrosis questionnaire-revised using multiple modelling approaches. Health and Quality of Life Outcomes. 2015;13:33.

7. Bradley JM, Blume SW, Balp MM, Honeybourne D, Elborn JS. Quality of life and healthcare utilisation in cystic fibrosis: A multicentre study. European Respiratory Journal. 2013;41(3):01.

8. KCE Reports 132a Cystic Fibrosis Neonatal Screening. 2010.9. Belgian average cost CF hospitalisations (APR-DRG=131, anno 2013).10. Belgian average cost heart and/or lung transplantation (APR-DRG=002, anno 2013).

FEV1 ≥ 70%

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tationFEV1

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RESULTS:Base case analysis compared LIS with AZLI in a cost-effectiveness analysis based on the NMA (3) from the health system perspective.

In the base case LIS was dominant vs. AZLI over two studied time horizons from the health care perspective (Table 3). LIS was associated with a gain in QALYs of 0.117 and 0.224 over three- and five-year time horizons, respectively, and was cost saving (-€515 and -€952, over three- and five-year time horizons, respectively) compared to AZLI.

Table 3. Results of the base case analysis: LIS vs. AZLI

Timeframe Three years Five yearsResults per patient LIS AZLI Incremental LIS AZLI IncrementalCost outcomesDrug costs €53,873 €53,661 €212 €78,965 €78,276 €689Maintenance costs €29,046 €29,194 -€148 €42,662 €43,015 -€353Minor exacerbation costs €171 €160 €10 €249 €236 €14Major exacerbation costs €1,087 €1,022 €64 €1,588 €1,501 €87Transplantation costs €745 €1,398 -€653 €961 €2,350 -€1,388Total - Health service €84,920 €85,435 -€515 €124,426 €125,377 -€952Efficacy outcomesQALYs 1.968 1.851 0.117 2.944 2.720 0.224LYs 2.948 2.948 0.001 4.387 4.382 0.004Number of minor exacerbations 3.904 3.674 0.230 5.779 5.465 0.314Number of major exacerbations 0.141 0.133 0.008 0.209 0.198 0.011Total number of exacerbations 4.045 3.806 0.238 5.988 5.663 0.325Cost-effectiveness - Health serviceCost per QALY gained Dominant DominantCost per exacerbation avoided €2,161 €2,925Cost per hospitalisation* avoided €61,924 €83,823

* hospitalisations due to pulmonary exacerbations. LY: Life years, QALY: Quality adjusted life year, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution

Table 2. Model assumptions and limitations

Assumption/Limitation JustificationThe transition probabilities between FEV1 severity levels after 24 weeks remain constant over the time horizon.

Lack of evidence on long-term efficacy

Patients do not switch treatments.

Absence of evidence on effectiveness

100% compliance. Lack of evidence of compliance information, therefore, equal and complete compliance was considered for all treatment options.

In the base case analysis LIS has no additional benefit in terms of patient survival.

Although evidence from registries and observational studies suggests that patients with lower FEV1% have a higher mortality hazard, the shape of the relationship between FEV1% and mortality hazard is not known.

Patients may only experience one exacerbation per cycle.

Only the first exacerbation experienced by the patient was measured in the MPEX-209 trial.

The population analysed differs from the licensed population of LIS (adults only) and AZLI (≥6 years).

The population included in the base case analyses reflects the population from the MPEX-209 trial, i.e. management of chronic pulmonary infections due to P. aeruginosa in patients ≥12 years old with CF. The model uses the patient characteristics (average age and baseline FEV1 percent predicted distribution) from the MPEX-209 trial (2). NMA conducted by Elborn et al 2016 (3) included all patients ≥6 years of age into the analyses. Therefore, the presented population represents a conservative estimate.

FEV1: Forced expiratory volume in 1 second, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution, NMA: Network meta-analysis

-8000 -6000 -4000 -2000 0 2000 4000 6000

FEV1 < 40% CF costs

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FEV1 40–69% to FEV1 < 40% AZLI

FEV1 40–69% proportion of major LIS

FEV1 40–69% proportion of major AZLI

Probability of transplantation

FEV1 40–69% CF costs

OR Exacerbation probability AZLI vs. LIS

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SimulationsCosts - Q0.025Costs - Q0.975QALYs - Q0.025QALYs - Q0.975Threshold