An economic evaluation was conducted of levofloxacin inhalation solution (LIS) compared to tobramycin in dry powder (TIP) and aztreonam lysine inhalation solution (AZLI) for treating chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients in Sweden. A Markov model was developed to estimate costs and quality-adjusted life years over 3 years, 5 years, and lifetime. The results found that over all time horizons, LIS was dominant compared to TIP, with lower costs and higher QALYs from a societal perspective. From a healthcare perspective, LIS was cost-effective compared to TIP.

1. 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.Theprobabilityofexperiencingamajorexacerbationwasalsoextracted
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 Source
Baseline characteristics
Average age per label population 30
MPEX-209 (2)
Average age full population 28
Patient 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%
Mortality
FEV1 health states
Weibull log lambda FEV1 -12.33
Tappenden et al. (1)
Weibull gamma FEV1 3.34
Post-transplant
Weibull log lambda post-transplant -12.33
Tappenden et al. (1)
Weibull gamma post-transplant 3.34
Association between FEV1 and mortality
HR for mortality 1
One year transplantation mortality
0-6 months post-transplant mortality 0.103
Whiting et al. (6)
6-12 months post-transplant mortality 0.103
Clinical inputs
Transition probabilities
LIS (in comparison vs. TIP and AZLI)
FEV1 ≥ 70% to FEV1 40–69% 0.129
Bayesian calibration
FEV1 40–69% to FEV1 ≥ 70% 0.069
FEV1 40–69% to FEV1 < 40% 0.018
FEV1 < 40% to FEV1 40–69% 0.143
TIP
FEV1 ≥ 70% to FEV1 40–69% TIS 0.51
Bayesian calibration
FEV1 40–69% to FEV1 ≥ 70% TIS 0.018
FEV1 40–69% to FEV1 < 40% TIS 0.119
FEV1 < 40% to FEV1 40–69% TIS 0.026
AZLI
FEV1 ≥ 70% to FEV1 40–69% TIS 0.417
Bayesian calibration
FEV1 40–69% to FEV1 ≥ 70% TIS 0.013
FEV1 40–69% to FEV1 < 40% TIS 0.081
FEV1 < 40% to FEV1 40–69% TIS 0.033
Exacerbations
Exacerbation probability LIS
FEV1 ≥ 70% exacerbation probability 0.527
MPEX-209 (2)FEV1 40–69% exacerbation probability 0.685
FEV1 < 40% exacerbation probability 0.696
Proportion of major LIS/TIP/AZLI
FEV1 ≥ 70% proportion of major 0.013
MPEX-209 (2)FEV1 40–69% proportion of major 0.013
FEV1 < 40% proportion of major 0.013
Exacerbation probability TIP
OR vs. LIS 2.566 NMA (3)
Exacerbation probability AZLI
OR vs. LIS 0.763 NMA (3)
Utilities
Health states utilities
FEV1 ≥ 70% utility 0.74
Acaster et al. (7)FEV1 40–69% utility 0.7
FEV1 < 40% utility 0.54
0-6 months transplantation utility 0.75
Whiting et al. (6)6-12 months transplantation utility 0.82
Post-transplant utility 0.82
Exacerbation utility decrement
Minor exacerbation utility decrement 0.06
Bradley et al. (8)
Major exacerbation utility decrement 0.25
Costs
CF costs
FEV1 ≥ 70% CF costs SEK 83,994
Whiting et al. (6)FEV1 40–69% CF costs SEK 83,994
FEV1 < 40% CF costs SEK 83,994
Post-transplant follow up costs
0-6 months post-transplant SEK 15,482
Socialstyrelsen (9-11)6-12 months post-transplant SEK 15,482
> 12 months post-transplant SEK 10,193
Exacerbation costs
Minor exacerbation costs SEK 5,418 Region Skåne 2015
(12)Major exacerbation costs SEK 81,270
Transplantation costs
Cost of transplant SEK 940,785
Socialstyrelsen 2016
(11)
Nebuliser costs
Nebuliser maintenance costs SEK 181.06
Indirect costs
Labour costs SEK 1,500 TLV 2015 (13)
Work absence 8.371
MPEX-209 (2)
Reference probability of working 0.574
FEV1 ≥ 70% probability of working 0.574
FEV1 40–69% probability of working 0.452
FEV1 < 40% probability of working 0.333
0-6 months post-transplant probability of working 0.333
6-12 months post-transplant probability of working 0.333
> 12 months post-transplant probability of working 0.333
Other
Transplantation
Probability of transplantation 0.009 Tappenden et al. (1)
Exacerbation duration
Minor exacerbation duration (weeks) 10 Assumption based on
Bradley 2013 (8)Major exacerbation duration (weeks) 10
Discount rates
Cost 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 Lifetime
Results per patient LIS TIP Incremental LIS TIP Incremental LIS TIP Incremental
Cost outcomes
Drug 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 174,230
Maintenance 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 118,396
Minor 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 17,245
Major 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 9,354
Transplantation 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 88,220
Indirect 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 304,883
Total - 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 127,075
Total - 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 177,808
Efficacy outcomes
QALYs 1.933 1.765 0.168 2.854 2.551 0.302 6.869 5.935 0.934
LYs 2.896 2.895 0.001 4.253 4.247 0.005 10.106 10.012 0.094
Number of minor exacerbations 3.835 5.016 -1.181 5.604 7.329 -1.725 13.108 16.291 -3.183
Number of major exacerbations 0.139 0.181 -0.043 0.203 0.265 -0.062 0.474 0.589 -0.115
Total number of exacerbations 3.973 5.197 -1.224 5.806 7.594 -1.788 13.582 16.880 -3.298
Cost-effectiveness - Societal
Cost per QALY gained Dominant Dominant Dominant
Cost per exacerbation avoided Dominant Dominant Dominant
Cost per hospitalisation* avoided Dominant Dominant Dominant
Cost-effectiveness - Health service
Cost per QALY gained SEK 3,477 SEK 7,516 SEK 190,316
Cost per exacerbation avoided SEK 477 SEK 1,272 SEK 53,910
Cost 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 Lifetime
Results per patient LIS AZLI Incremental LIS AZLI Incremental LIS AZLI Incremental
Cost outcomes
Drug 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 221,348
Maintenance 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 95,242
Minor 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 5,883
Major 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 3,191
Transplantation 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 71,709
Indirect 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 265,070
Total - 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 11,115
Total - 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 253,955
Efficacy outcomes
QALYs 1.933 1.818 0.115 2.854 2.639 0.215 6.869 6.140 0.729
LYs 2.896 2.895 0.001 4.253 4.249 0.004 10.106 10.031 0.075
Number of minor exacerbations 3.835 3.608 0.227 5.604 5.298 0.306 13.108 12.022 1.086
Number of major exacerbations 0.139 0.130 0.008 0.203 0.192 0.011 0.474 0.435 0.039
Total number of exacerbations 3.973 3.738 0.235 5.806 5.490 0.317 13.582 12.457 1.125
Cost-effectiveness - Societal
Cost per QALY gained Dominant Dominant Dominant
Cost per exacerbation avoided SEK 33,960 SEK 80,894 SEK 9,878
Cost per hospitalisation* avoided SEK 973,180 SEK 2,318,132 SEK 283,071
Cost-effectiveness - Health service
Cost per QALY gained SEK 309,547 SEK 243,603 SEK 348,375
Cost per exacerbation avoided Dominated Dominated Dominated
Cost 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
Aone-waysensitivityanalysiswasconductedinordertoidentifymodelparameters
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:
• ThismodelsimulatedthediseaseprogressionofCFpatientsasmeasured
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.
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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.
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000014&docType=6 Accessed March 2016.
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&docType=6 Accessed March 2016
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12. Region Skåne (2015). Lungmedicin. Sluten vård. VD010 Omvårdnadsdag.
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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 bound
Lower 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 bound
Lower 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
IncrementalCosts
Incremental QALYs
Simulations
Costs - Q0.025
Costs - Q0.975
QALYs - Q0.025
QALYs - Q0.975
Threshold
FEV1
≥ 70%
predicted
FEV1
< 40%
predicted
Dead
Post-
transplant
Transplan-
tation
FEV1
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
IncrementalCosts
Incremental QALYs
Simulations
Costs - Q0.025
Costs - Q0.975
QALYs - Q0.025
QALYs - Q0.975
Threshold