OBJECTIVES:To conduct an economic evaluation of levofloxacin inhalation solution (LIS) compared to tobramycin in dry powder (TIP), and aztreonam lysine inhalation solution (AZLI) in Sweden for the treatment of chronic Pseudomonas aeruginosa lung infection in 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. The base case analysis was conducted from both Swedish societal and health care perspectives at three time horizons (3-years, 5-years, and lifetime). Costs were in 2016 Swedish Kronor (1 SEK≈0.11 Euro). 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.

Figure 1. Model structure

FEV1: Forced expiratory volume in 1 second

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 comparators (AZLI and TIP). 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 network meta-analysis (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.

Costs of comparators were calculated based on the drug prices derived from the Swedish national formulary of drugs and drug dosages (4, 5). The cost of nebuliser was not taken into account as it was considered equal between the treatments. It was also assumed that aztreonam lysine and LIS treatment costs included the cost of nebuliser maintenance.

All input parameters are presented in Table 1.

Table 1. Input parameters

Base case SourceBaseline characteristicsAverage age per label population 30

MPEX-209 (2) Average age full population 28Patient distribution at baseline per label population (18+)% of patients FEV1 ≥ 70% 22%

MPEX-209 (2)% of patients FEV1 40–69% 52%% of patients FEV1 < 40% 26%Patient distribution at baseline full population (12+)% 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 One year transplantation mortality0-6 months post-transplant mortality 0.103

Whiting et al. (6)6-12 months post-transplant mortality 0.103Clinical inputsTransition probabilitiesLIS (in comparison vs. TIP and AZLI)FEV1 ≥ 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% 0.143TIPFEV1 ≥ 70% to FEV1 40–69% TIS 0.51

Bayesian calibrationFEV1 40–69% to FEV1 ≥ 70% TIS 0.018FEV1 40–69% to FEV1 < 40% TIS 0.119FEV1 < 40% to FEV1 40–69% TIS 0.026AZLIFEV1 ≥ 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 0.685FEV1 < 40% exacerbation probability 0.696Proportion of major LIS/TIP/AZLIFEV1 ≥ 70% proportion of major 0.013

MPEX-209 (2)FEV1 40–69% proportion of major 0.013FEV1 < 40% proportion of major 0.013Exacerbation probability TIPOR vs. LIS 2.566 NMA (3)Exacerbation probability AZLIOR vs. LIS 0.763 NMA (3)UtilitiesHealth states utilitiesFEV1 ≥ 70% utility 0.74

Acaster et al. (7)FEV1 40–69% utility 0.7FEV1 < 40% utility 0.540-6 months transplantation utility 0.75

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

Bradley et al. (8)Major exacerbation utility decrement 0.25CostsCF costsFEV1 ≥ 70% CF costs SEK 83,994

Whiting et al. (6)FEV1 40–69% CF costs SEK 83,994FEV1 < 40% CF costs SEK 83,994Post-transplant follow up costs0-6 months post-transplant SEK 15,482

Socialstyrelsen (9-11)6-12 months post-transplant SEK 15,482> 12 months post-transplant SEK 10,193Exacerbation costsMinor exacerbation costs SEK 5,418 Region Skåne 2015

(12)Major exacerbation costs SEK 81,270Transplantation costs

Cost of transplant SEK 940,785 Socialstyrelsen 2016 (11)

Nebuliser costsNebuliser maintenance costs SEK 181.06 Indirect costsLabour costs SEK 1,500 TLV 2015 (13)Work absence 8.371

MPEX-209 (2)

Reference probability of working 0.574FEV1 ≥ 70% probability of working 0.574FEV1 40–69% probability of working 0.452FEV1 < 40% probability of working 0.3330-6 months post-transplant probability of working 0.3336-12 months post-transplant probability of working 0.333> 12 months post-transplant probability of working 0.333OtherTransplantationProbability of transplantation 0.009 Tappenden et al. (1)Exacerbation durationMinor exacerbation duration (weeks) 10 Assumption based on

Bradley 2013 (8)Major exacerbation duration (weeks) 10Discount ratesCost outcomes discount 3%

Efficacy outcomes discount 3%

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

Cost-effectiveness of Levofloxacin Inhalation Solution vs. Aztreonam Inhalation Solution and Tobramycin dry powder for inhalation in Cystic fibrosis patients in Sweden G. Medic1; K. Franck-Larsson1; M. Wille1; S. Rodahl1; M. Hemels1

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

The following analyses were conducted:• Base case analysis One compared LIS with TIP in a cost-effectiveness analysis

based on the NMA in the full population• Base case analysis Two compared LIS with AZLI in a cost-effectiveness

analysis based on the NMA in the full population.

Several scenario analyses were also conducted to specifically explore the uncertainty surrounding several parameters:• Scenario 1: Alternative source for utilities from Tappenden et al (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 extrapolation approach (FEV1 % transition probabilities and exacerbation rate for LIS set equal to the comparator after 5 years).

• Scenario 3: Alternative discount rates– Scenario 3.1:

discount rate costs = 0% / discount rate health outcomes = 0%– Scenario 3.2:

discount rate costs = 5% / discount rate health outcomes = 5%– Scenario 3.3:

discount rate costs = 3% / discount rate health outcomes = 0%.

Model assumptions and limitations are summarised in Table 2.

Table 2. Model assumptions and limitations

Assumption/ Limitation

Justification

The transition proba-bilities 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 anal-ysis LIS has no addi-tional 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 ex-perience one exacer-bation per cycle.

Only the first exacerbation experienced by the patient was measured in the MPEX-209 trial. (2)

The population analysed differs from the licensed population of LIS (adults only), AZLI (≥6 years) and TIP (≥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, TIP: Tobramycin in dry powder, AZLI: Aztreonam lysine inhalation solution, NMA: Network meta-analysis

RESULTS:LIS was dominant vs. TIP over the three time horizons from the societal perspective and associated with a gain in QALYs of 0.168, 0.320 and 0.934 and cost saving of SEK 51,968, SEK 91,162 and SEK 127,075, respectively. From the health care perspective, LIS was cost-effective vs. TIP (at a cost-effectiveness threshold of SEK 500,000 per QALY), yielding ICERs of SEK 3,477, SEK 7,516 and SEK 190,316 over three time horizons, respectively.

Table 3. Results of the base case analysis: LIS vs. TIP full population

Timeframe Three years Five years LifetimeResults per patient LIS TIP Incremental LIS TIP Incremental LIS TIP IncrementalCost outcomesDrug costs SEK 467,695 SEK 448,058 SEK 19,637 SEK 685,534 SEK 652,539 SEK 32,995 SEK 1,614,970 SEK 1,440,740 SEK 174,230Maintenance costs SEK 524,275 SEK 521,887 SEK 2,388 SEK 768,626 SEK 760,827 SEK 7,799 SEK 1,812,567 SEK 1,694,171 SEK 118,396Minor exacerbation costs SEK 20,774 SEK 27,174 -SEK 6,400 SEK 30,359 SEK 39,705 -SEK 9,346 SEK 71,015 SEK 88,260 -SEK 17,245Major exacerbation costs SEK 11,268 SEK 14,739 -SEK 3,471 SEK 16,467 SEK 21,536 -SEK 5,069 SEK 38,519 SEK 47,873 -SEK 9,354Transplantation costs SEK 9,714 SEK 21,285 -SEK 11,570 SEK 12,541 SEK 36,646 -SEK 24,105 SEK 21,004 SEK 109,224 -SEK 88,220Indirect costs SEK 99,269 SEK 151,821 -SEK 52,552 SEK 141,483 SEK 234,918 -SEK 93,435 SEK 314,718 SEK 619,600 -SEK 304,883Total - Societal SEK 1,132,996 SEK 1,184,963 -SEK 51,968 SEK 1,655,011 SEK 1,746,173 -SEK 91,162 SEK 3,872,794 SEK 3,999,869 -SEK 127,075Total - Health service SEK 1,033,727 SEK 1,033,143 SEK 584 SEK 1,513,528 SEK 1,511,254 SEK 2,273 SEK 3,558,076 SEK 3,380,269 SEK 177,808Efficacy outcomesQALYs 1.933 1.765 0.168 2.854 2.551 0.302 6.869 5.935 0.934LYs 2.896 2.895 0.001 4.253 4.247 0.005 10.106 10.012 0.094Number of minor exacerbations 3.835 5.016 -1.181 5.604 7.329 -1.725 13.108 16.291 -3.183Number of major exacerbations 0.139 0.181 -0.043 0.203 0.265 -0.062 0.474 0.589 -0.115Total number of exacerbations 3.973 5.197 -1.224 5.806 7.594 -1.788 13.582 16.880 -3.298Cost-effectiveness - SocietalCost per QALY gained Dominant Dominant DominantCost per exacerbation avoided Dominant Dominant DominantCost per hospitalisation* avoided Dominant Dominant DominantCost-effectiveness - Health serviceCost per QALY gained SEK 3,477 SEK 7,516 SEK 190,316Cost per exacerbation avoided SEK 477 SEK 1,272 SEK 53,910Cost per hospitalisation* avoided SEK 13,674.49 SEK 36,446.19 SEK 1,544,870.32

* hospitalisations due to pulmonary exacerbations: Abbreviations: LY: Life years, QALY: Quality adjusted life year, LIS: Levofloxacin inhalation solution, TIP: Tobramycin in dry powder

Table 4. Results of the base case analysis: LIS vs. AZLI full population

Timeframe Three years Five years LifetimeResults per patient LIS AZLI Incremental LIS AZLI Incremental LIS AZLI IncrementalCost outcomesDrug costs SEK 467,695 SEK 427,379 SEK 40,317 SEK 685,534 SEK 623,426 SEK 62,108 SEK 1,614,970 SEK 1,393,622 SEK 221,348Maintenance costs SEK 524,275 SEK 522,526 SEK 1,749 SEK 768,626 SEK 762,836 SEK 5,790 SEK 1,812,567 SEK 1,717,325 SEK 95,242Minor exacerbation costs SEK 20,774 SEK 19,547 SEK 1,228 SEK 30,359 SEK 28,702 SEK 1,657 SEK 71,015 SEK 65,132 SEK 5,883Major exacerbation costs SEK 11,268 SEK 10,602 SEK 666 SEK 16,467 SEK 15,568 SEK 899 SEK 38,519 SEK 35,328 SEK 3,191Transplantation costs SEK 9,714 SEK 18,230 -SEK 8,516 SEK 12,541 SEK 30,647 -SEK 18,105 SEK 21,004 SEK 92,713 -SEK 71,709Indirect costs SEK 99,269 SEK 142,688 -SEK 43,419 SEK 141,483 SEK 219,468 -SEK 77,985 SEK 314,718 SEK 579,788 -SEK 265,070Total - Societal SEK 1,132,996 SEK 1,140,971 -SEK 7,975 SEK 1,655,011 SEK 1,680,647 -SEK 25,637 SEK 3,872,794 SEK 3,883,909 -SEK 11,115Total - Health service SEK 1,033,727 SEK 998,283 SEK 35,444 SEK 1,513,528 SEK 1,461,180 SEK 52,348 SEK 3,558,076 SEK 3,304,121 SEK 253,955Efficacy outcomesQALYs 1.933 1.818 0.115 2.854 2.639 0.215 6.869 6.140 0.729LYs 2.896 2.895 0.001 4.253 4.249 0.004 10.106 10.031 0.075Number of minor exacerbations 3.835 3.608 0.227 5.604 5.298 0.306 13.108 12.022 1.086Number of major exacerbations 0.139 0.130 0.008 0.203 0.192 0.011 0.474 0.435 0.039Total number of exacerbations 3.973 3.738 0.235 5.806 5.490 0.317 13.582 12.457 1.125Cost-effectiveness - SocietalCost per QALY gained Dominant Dominant DominantCost per exacerbation avoided SEK 33,960 SEK 80,894 SEK 9,878Cost per hospitalisation* avoided SEK 973,180 SEK 2,318,132 SEK 283,071Cost-effectiveness - Health serviceCost per QALY gained SEK 309,547 SEK 243,603 SEK 348,375Cost per exacerbation avoided Dominated Dominated DominatedCost per hospitalisation* avoided Dominated Dominated Dominated

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

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). Hazard ratio for mortality and FEV1 % predicted CF costs <40% are the two input parameters with the greatest impact on the incremental costs for LIS vs. TIP in the full population.

Figure 2. Tornado chart; LIS vs. TIP full population; Lifetime horizon – Incremental costs

FEV1: Forced expiratory volume in 1 second, LIS: Levofloxacin inhalation solution, TIP: Tobramycin in dry powder

Figure 3. Results of the PSA LIS vs. TIP full population; Lifetime horizon – Incremental Cost-Effectiveness Plane

PSA: Probabilistic sensitivity analysis, LIS: Levofloxacin inhalation solution, TIP: Tobramycin in dry powder

In all scenarios, conclusions are similar to the base case analysis: LIS was dominant compared to TIP over 3-, 5- years and lifetime horizons from the societal perspective.

In addition, LIS was also dominant vs. AZLI in the full population over three studied time horizons from the societal perspective. It was associated with a predicted gain in QALYs of 0.115, 0.215 and 0.729 and cost savings, respec-tively. From the health care perspective, LIS was cost-effective compared to AZLI yielding ICERs of SEK 309,547, SEK 243,603 and SEK 348,375 over three time horizons, respectively.

The results of OWSA for LIS vs. AZLI are presented in form of tornado chart showing the difference in the analysed outcome comparing with the base case (Figure 4). Hazard ratio for mortality and FEV1 % predicted CF costs <40% are the two input parameters with the greatest impact on the incremental costs for LIS vs. AZLI in the full population.

Figure 4. Tornado chart; LIS vs. AZLI full population; Lifetime horizon – Incremental costs

FEV1: Forced expiratory volume in 1 second, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution

Figure 5. Results of the PSA LIS vs. AZLI full population; Lifetime horizon – Incremental Cost-Effectiveness Plane

PSA: Probabilistic sensitivity analysis, LIS: Levofloxacin inhalation solution, AZLI: Aztreonam lysine inhalation solution

In all scenarios, conclusions are similar to the base case analysis: LIS was dominant compared to AZLI except the Scenario 2 and 3.1 over a lifetime horizon where it was cost-effective under the threshold of SEK 500,000.

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

by the decrease in FEV1 percent predicted.

• Sensitivity analyses showed that the ICER was mainly sensitive to transition probabilities between the FEV1 % health states, the utilities and costs corresponding to the FEV1 health states.

• LIS was found dominant compared with TIP and AZLI from the social perspective and cost-effective from the healthcare perspective at the cost-effectiveness threshold of SEK 500,000.

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. FASS (2016) TOBI Podhaler Produktresumé. Available at: http://www.fass.se/LIF/product?23&userType=0&nplId=20100127 000014&docType=6 Accessed March 2016.

5. FASS (2016) Cayston Produktresumé. Available at: http://www.fass.se/LIF/product?16&userType=0&nplId=20080422000042 &docType=6 Accessed March 2016

6. 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.

7. 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.

8. 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.

9. Socialstyrelsen (2016b). Referensvikter för slutenvårdsgrupper, NordDRG 2016. DRG D50C Fynd/symptom andningsorg U.10. Socialstyrelsen (2016a). Referensvikter för slutenvårdsgrupper, NordDRG 2016. DRG D50C Fynd/symptom andningsorg K.11. Socialstyrelsen (2016). Referensvikter för slutenvårdsgrupper, NordDRG 2016. DRG D01N Lungtransplantation.12. Region Skåne (2015). Lungmedicin. Sluten vård. VD010 Omvårdnadsdag.13. TLV (2015): Metodbeskrivning för att beräkna produktionsvärde. 2015. .

HR mortality

FEV1 < 40% CF costs

FEV1 40–69% CF costs

FEV1 ≥ 70% CF costs

FEV1 < 40% probability of working

FEV1 40–69% to FEV1 ≥ 70% LIS

FEV1 ≥ 70% to FEV1 40–69% LIS

FEV1 ≥ 70% probability of working

Probability of transplantation

FEV1 40–69% probability of working

Higher boundLower bound

-1000000 -500000 0 500000 1000000 1500000

HR mortality

FEV1 < 40% CF costs

FEV1 ≥ 70% CF costs

FEV1 < 40% probability of working

FEV1 40–69% CF costs

FEV1 40–69% to FEV1 ≥ 70% LIS

FEV1 ≥ 70% to FEV1 40–69% LIS

FEV1 ≥ 70% probability of working

Probability of transplantation

Labour costs

Higher boundLower bound

-400000 0 400000 800000 1200000

-1.500.000

-1.000.000

-500.000

0

500.000

1.000.000

1.500.000

-1,500 -1,000 -0,500 0,000 0,500 1,000 1,500 2,000 2,500 3,000 3,500

Incr

emen

tal C

osts

Incremental QALYs

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

FEV1 ≥ 70%

predicted

FEV1 < 40%

predictedDeadPost-

transplantTransplan-

tationFEV1

40-69% predicted

On treatment Off treatment

-2.000.000

-1.500.000

-1.000.000

-500.000

0

500.000

1.000.000

1.500.000

2.000.000

-1,000 -0,500 0,000 0,500 1,000 1,500 2,000 2,500 3,000

Incr

emen

tal C

osts

Incremental QALYs

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