1. 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
consideredforpatientsinthe“Transplantation”state.Theimpactoftheassociation
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 Source
Baseline characteristics
Average 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%
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
Transplantation mortality
0-6 months post-transplant mortality 0.103
Whiting et al. (5)
6-12 months post-transplant mortality 0.103
Clinical inputs
Transition probabilities
LIS
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
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 MPEX-209 (2)
FEV1 < 40% exacerbation probability 0.696 MPEX-209 (2)
Proportion of major LIS
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 AZLI
OR 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 0.013
FEV1 < 40% proportion of major 0.013
Utilities
Health states utilities
FEV1 ≥ 70% utility 0.74
Acaster et al. (6)FEV1 40–69% utility 0.7
FEV1 < 40% utility 0.54
0-6 months transplantation utility 0.75
Whiting et al. (5)6-12 months transplantation utility 0.82
Post-transplant utility 0.82
Exacerbation utility decrement
Minor exacerbation utility decrement 0.06
Bradley et al. (7)
Major exacerbation utility decrement 0.25
Costs
CF costs
FEV1 ≥ 70% CF costs € 4,594.84
KCE 2010 (8)FEV1 40–69% CF costs € 4,594.84
FEV1 < 40% CF costs € 4,594.84
Post-transplant follow up costs
0-6 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 Inhalation
Solution vs. Aztreonam Inhalation Solution
in Cystic fibrosis patients in Belgium
G. Medic1
; M. Westen1
; M. Wille1
; M. Hemels1
1
Raptor Pharmaceuticals, Naritaweg 165; 1043BW Amsterdam; The Netherlands
Base case Source
Exacerbation costs
Minor exacerbation costs € 44.47 Expert opinion
Major exacerbation costs € 7,836.96 Belgian average cost CF hospitali-
sations (9)
Transplantation costs
Cost of transplant € 72,125.80 Belgian average cost heart and/
or lung transplantation (APR-
DRG=002, anno 2013) (10)
Other
Transplantation
Probability of transplantation 0.009 Tappenden 2014. (1)
Exacerbation duration
Minor exacerbation duration (weeks) 10 Assumption based on Bradley et
al. (7)Major exacerbation duration (weeks) 10
Discount rates
Cost 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.
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). 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
costs
FEV1: 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 Plane
PSA: 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 Curve
PSA: 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:
• ThismodelsimulatedthediseaseprogressionofCFpatientsasmeasured
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.
REFERENCES
1. 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%
predicted
FEV1
< 40%
predicted
Dead
Post-
transplant
Transplan-
tation
FEV1
40-69%
predicted
On treatment Off treatment
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 years
Results per patient LIS AZLI Incremental LIS AZLI Incremental
Cost outcomes
Drug costs €53,873 €53,661 €212 €78,965 €78,276 €689
Maintenance costs €29,046 €29,194 -€148 €42,662 €43,015 -€353
Minor exacerbation costs €171 €160 €10 €249 €236 €14
Major exacerbation costs €1,087 €1,022 €64 €1,588 €1,501 €87
Transplantation costs €745 €1,398 -€653 €961 €2,350 -€1,388
Total - Health service €84,920 €85,435 -€515 €124,426 €125,377 -€952
Efficacy outcomes
QALYs 1.968 1.851 0.117 2.944 2.720 0.224
LYs 2.948 2.948 0.001 4.387 4.382 0.004
Number of minor exacerbations 3.904 3.674 0.230 5.779 5.465 0.314
Number of major exacerbations 0.141 0.133 0.008 0.209 0.198 0.011
Total number of exacerbations 4.045 3.806 0.238 5.988 5.663 0.325
Cost-effectiveness - Health service
Cost per QALY gained Dominant Dominant
Cost per exacerbation avoided €2,161 €2,925
Cost 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 Justification
The 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
FEV1 ≥ 70% CF costs
HR mortality
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
FEV1 < 40% proportion of major
Higher bound
Lower bound
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 50 100 150 200 250 300 350 400 450 500
Probability
Incremental Cost Effectiveness Ratio (€1,000)
-40.000
-30.000
-20.000
-10.000
0
10.000
20.000
-0,200 -0,100 0,000 0,100 0,200 0,300 0,400 0,500 0,600
IncrementalCosts
Incremental QALYs
Simulations
Costs - Q0.025
Costs - Q0.975
QALYs - Q0.025
QALYs - Q0.975
Threshold