Pediatric Pulmonology 46:230–238 (2011)
Tobramycin Inhalation Powder for P. aeruginosa
Infection in Cystic Fibrosis: The EVOLVE Trial
Michael W. Konstan, MD,1* David E. Geller, MD,2Predrag Minic ´, MD,3
Florian Brockhaus, PhD,4Jie Zhang, PhD,5and Gerhild Angyalosi, MD4
infection in cystic fibrosis (CF) patients. We evaluated the efficacy and safety of a novel, light-
porous particle, dry-powder formulation of tobramycin, which was developed to improve delivery
efficiency to the airways and substantially reduce the delivery time. In this randomized, double-
blind study, patients with CF (age 6–21 years) received tobramycin inhalation powder (112mg
tobramycin) twicedaily(n¼46)or placebo(n¼49)via the T-326 Inhalerfor onecycle, followedby
two open-label cycles (all patients). Cycles were 28 days on, 28 days off treatment. The primary
28 of Cycle 1. The study was terminated early based on positive results in the interim analysis.
Tobramycin inhalation powder significantly improved FEV1% predicted versus placebo at Day 28
over time. Tobramycin inhalation powder also reduced sputum P. aeruginosa density, respiratory-
related hospitalization and antipseudomonal antibiotic use versus placebo. The most common
versus tobramycin inhalation powder (13.0%) in Cycle 1. Tobramycin inhalation powder was not
associated with ototoxicity or nephrotoxicity. Administration time was between 4 and 6min. In
offer an important treatment option to decrease the treatment burden of CF pseudomonas lung
infections. Pediatr Pulmonol. 2011; 46:230–238.
? 2010 Wiley-Liss, Inc.
Key words: cystic fibrosis; tobramycin inhalation powder; Pseudomonas aeruginosa.
Funding source: Novartis Pharma AG, Basel, Switzerland
The majority of individuals with cystic fibrosis (CF)
develop chronic pulmonary infections that are difficult
to treat.1Pseudomonas aeruginosa is the predominant
pathogen associated with progressive loss of lung
function, as well as morbidity and mortality in patients
with CF.2–5Antibiotics by inhalation, including the
aminoglycoside tobramycin, are commonly used to treat
Tobramycin inhalation solution (TIS; TOBI1) has been
shown to significantly improve lung function, as well as
life in patients with CF.9–12
Tobramycin inhalation solution 300mg/5ml twice
with a suitable compressor, is currently approved for the
treatment of chronic P. aeruginosa pulmonary infections
in patients with CF aged 6 years and older with forced
expiratory volume in 1sec (FEV1) ?25 to ?75%
predicted.13Both US and European CF treatment guide-
lines recommend the use of TIS for treatment of
P. aeruginosa pulmonary infection in CF patients.14,15
1Rainbow Babies and Children’s Hospital, and Case Western Reserve
University School of Medicine, Cleveland, Ohio.
2Nemours Children’s Clinic, Orlando, Florida.
3Mother & Child Health Institute, Belgrade, Serbia.
4Novartis Pharma AG, Basel, Switzerland.
5Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Clinical Trials.gov Identifier: NCT00125346.
Grant sponsor: Novartis Pharma AG, Basel, Switzerland.
*Correspondence to: Michael W. Konstan, MD, Director, The LeRoy W.
Matthews Cystic Fibrosis Center, Rainbow Babies and Children’s Hospital,
11100 Euclid Avenue, Cleveland, OH 44106.
Received 7 April 2010; Revised 9 June 2010; Accepted 6 July 2010.
Published online 20 October 2010 in Wiley Online Library
? 2010 Wiley-Liss, Inc.
Administration time for TIS is approximately 15min per
nebulizer.16To reduce the treatment burden for patients, a
new drug-device combination using an inhalation powder
formulation of tobramycin is being developed. Tobramy-
cin inhalation powder (TIPTM) is manufactured using
Novartis PulmoSphere1technology, an emulsion-based
spray drying process that yields spherical hollow-porous
particles (Fig. 1a). The new inhalation powder formula-
tion of tobramycin is delivered via the T-326 Inhaler
(Novartis Pharmaceuticals, San Carlos, CA; Fig. 1b).16
The device, which does not require a power source or
electronics, was designed to enhance the delivery of the
drug to the lung and shorten administration time. This
may translate into increased patient adherence and
of tobramycin inhalation powder of 112mg b.i.d. was
selected from a Phase 1 dose-finding study.16The present
Phase 3 study (EVOLVE) was designed to assess the
efficacy and safety of this new tobramycin inhalation
powder formulation for treating CF patients with
P. aeruginosa infection.
This study was conducted between September 2005
and February 2007 in 38 centers in Europe (Bulgaria,
Lithuania, Serbia), Latin America (Argentina, Brazil,
Chile, Mexico), and the United States. The study was
Ethics Committee for each center and was conducted in
accordance with the Declaration of Helsinki. Written
informed consent was obtained from each patient or their
legal representative prior to randomization.
CF patients aged 6–21 years with FEV1?25 to ?80%
predicted based on Knudson criteria,17were eligible for
enrollment. Diagnosis was confirmed by at least one
clinical feature of CF plus sweat chloride test ?60mEq/L
mutations in each cystic fibrosis transmembrane con-
ductance regulator [CFTR] gene or abnormal nasal
transepithelial potential difference (characteristic of
CF). Eligible patients were also required to have a posi-
tive sputum or throat culture for P. aeruginosa within
6 months of screening, and a positive sputum culture for
P. aeruginosa at the screening visit.
Patients were excluded if they had positive cultures for
Burkholderia cepacia within 2 years prior to screening or
at screening; hemoptysis >60cc at any time within
30 days of study drug administration; aminoglycoside
hypersensitivity or adverse reaction to inhaled anti-
biotics; serum creatinine ?2mg/dl, blood urea nitrogen
?40mg/dl, or abnormal urinalysis (?2þ proteinuria).
During the study, patients were allowed to use broncho-
dilators, macrolide antibiotics, dornase alfa, and inhaled
steroids provided these were started at least 28 days prior
to study drug administration. However, patients were
excluded if they had received inhaled antipseudomonal
antibiotics within 4 months prior to screening; systemic
antipseudomonal antibiotics within 28 days prior to study
drug administration and loop diuretics within 7 days of
study drug administration. If patients required treatment
were required to withdraw from the study.
This randomized two-arm trial comprised three cycles;
each cycle consisted of 28 days on treatment followed by
28 days off treatment. Cycle 1 was double-blind and
placebo-controlled with patients randomized 1:1 to
tobramycin inhalation powder (112mg) or placebo, both
administered twice daily via the T-326 Inhaler. During
Cycle 1 patients received tobramycin inhalation powder
(four capsules each containing tobramycin 28mg to be
inhaled twice daily) or matching placebo capsules. The
placebo was made from the excipients used in the spray-
drying process to manufacture the study drug; distear-
ylphosphatidylcholine (DSPC) and calcium chloride.
Fig. 1. Tobramycin inhalation powder: a novel, light-porous
inhaler. a: Hollow, porous particles of tobramycin inhalation
powder; b: the T-326 Inhaler.
Tobramycin Inhalation Powder in Cystic Fibrosis 231
tobramycin inhalation powder for two additional cycles
(Cycles 2 and 3). The total study duration was 24 weeks.
The primary efficacy measure was relative change in
FEV1 % predicted from baseline (Day 1 pre-dose
measurement) to end of Cycle 1 dosing (Day 28 pre-dose
measurement) versus placebo. Other efficacy measures
included change in sputum P. aeruginosa density [colony
forming units (CFU) per gram of sputum], P. aeruginosa
susceptibility to tobramycin [minimum inhibitory con-
centrations (MIC)], antipseudomonal antibiotic use, and
Safety assessments included the incidence and severity
of all adverse events (AEs) throughout the study, changes
invital signs, hematology, blood chemistry, urine protein,
audiology (at selected sites), and the presence of airway
reactivity secondary to the study drug (relative change in
FEV1% predicted from pre-dose to 30min post-dose). In
addition, serum tobramycin concentrations were meas-
ured in Cycles 1 and 2, or earlier in the case of early
termination from the study.
Lung function was measured by spirometry in accord-
ance with established guidelines.18The same spirometer
was used at each study visit. FEV1was measured and
expressed as a percentage of predicted normal values;
regression equations were used to calculate predicted
values according to Knudson criteria.17
Pseudomonas aeruginosa Susceptibility Testing
Expectorated sputum or throat swabs were sent by
courier to a central laboratory (ICON Central Labora-
tories) for analysis. Sputum samples were cultured
quantitatively and throat swabs were cultured semi-
MICs for tobramycin were established for all P. aerugi-
nosa isolates via a Sensititre custom panel CMP4DCHS
(CGI). Interpretation was based on current National
Committee on Clinical Laboratory Standards (NCCLS)
guidelines. Susceptibility testing was performed for each
distinctive P. aeruginosa phenotype (mucoid, non-
mucoid, and small colony variant).
A sample size of 140 patients (70 per group) was
estimated to provide 90% power at two-sided 0.05
significance level to detect a treatment difference of
11% in mean (assuming 20% standard deviation) relative
change of FEV1% predicted in Cycle 1 (baseline to
The study included a planned interim analysis by an
once 80 patients had completed dosing in Cycle 1. The
objectives were to (a) estimate the common standard
deviation for sample size re-estimation, (b) evaluate
efficacy of tobramycin inhalation powder versus placebo
for potential early termination of the study, and (c) assess
safety in terms of AEs, airway reactivity, and broncho-
spasm. After reviewing the results, which showed a
statistically significant benefit of tobramycin inhalation
powder over placebo, the DMC recommended the trial be
terminated early as pre-defined stopping criteria were
fulfilled. Subsequently, concerns were raised regarding
the quality of spirometry data from some Latin American
centers. An expert panel of pulmonologists was therefore
set up to review, in a blinded manner, the spirometry data
from all Latin American Centers in the original interim
analysis. The expert panel pre-defined a set of quality
criteria to evaluate the adequacy of the FEV1data: (1)
patients must have acceptable calibrations at screening
day, Days 1, 8, and 28; (2) In addition to calibrations,
patients must satisfy quality review at baseline (screening
dose of Cycle 1). After reviewing the source spirometry
data from all Latin American centers, the expert panel
recommended that 18 patients (10 TIP-treated and 8
placebo-treated patients) from the original interim
analysis should be excluded, due to unacceptable calibra-
tion of the spirometer or unacceptable FEV1data quality.
Subsequently, a sensitivity interim analysis (SIA) was
performed by the DMC that excluded the 18 patients
identified; this subpopulation (n¼61) is referred to as the
modified intent-to-treat (mITT) population. Based on the
results of the SIA, the DMC again recommended the trial
be terminated early.
The primary efficacy analysis was based on the mITT
population. The primary efficacy measure was assessed
using an analysis of covariance (ANCOVA) model;
factors of treatment, baseline FEV1% predicted, age,
and region were included in the model. Due to interim
analysis, the statistical significance level was set at
0.0044 for the SIA. All other efficacy measures used the
all-treated patient population (includes all patients
randomized who received at least one capsule of study
medication, mITT population) and are reported descrip-
tively with no formal statistical testing. All final analyses
are based on observed data with no imputation per-
formed for missing data. All reported AEs were recorded.
Safety measures are summarized descriptively. The
SAS1software version 8.2 (SAS Institute, Cary, NC)
232 Konstan et al.
Baseline Demographic and Clinical Characteristics
In total, 102 patients were randomized and 95 patients
were treated (Fig. 2): 46 patients received tobramycin
during Cycle 1 before all patients received open-label
tobramycin inhalation powder for two additional cycles.
Both treatment groups had generally high levels of
of used and unused capsules returned per patient, and
percentage of completed scheduled study visits. In Cycle
1, 91% adherence was observed for the patients in the
tobramycin inhalation powder group and 89% in the
showed greater than 95% adherence.
In the all-treated patient population, baseline demo-
graphics andclinical characteristics weresimilarbetween
the two treatment groups (Table 1). Baseline demo-
Use of inhaled antipseudomonal antibiotics within the
groups: tobramycin inhalation powder group, 4.3%;
placebo group, 4.1% (in accordance with the study
inclusion criteria, none of the enrolled patients had used
inhaled antipseudomonal antibiotics within the last
4 months prior to screening). During the study, concom-
itant therapy was used by 91.3% of patients in the
tobramycin inhalation powder group and 98.0% in the
placebo group. Dornase alfa was used by 58.7% and
and placebo, respectively. Other commonly used con-
comitant medications were: pancreatic enzyme prepara-
tions, 73.9% in the tobramycin inhalation powder group,
and 85.7% in the placebo group (bioglan panazyme,
pancrealipase), and selective b2-adrenoreceptor agonists,
45.7% in the tobramycin inhalation powder group, and
61.2%inthe placebo group(mostfrequentlysalbutamol).
Tobramycin inhalation powder (112mg tobramycin
b.i.d.) significantly improved FEV1% predicted from
baseline to Day 28 of Cycle 1 compared with placebo in
the mITT population (least squares mean difference 13.3,
95% CI: 5.31–21.28; P¼0.0016). The results of ad hoc
analyses performed using the original interim analysis
ITT population (including patients from Latin American
(data not shown). The relative change from baseline in
FEV1 % predicted over the three cycles is shown in
Figure 3. Improvements in FEV1 with tobramycin
inhalation powder in Cycle 1 were maintained for all
Fig. 2. Study disposition (all randomized patients). *Includes moved, intolerant of inhaler,
non-compliance, and self-discontinuation; TIP¼tobramycin inhalation powder.
Tobramycin Inhalation Powder in Cystic Fibrosis233
three cycles. When patients were switched from placebo
to tobramycin inhalation powder in Cycle 2, FEV1%
predicted increased to the level observed in the tobramy-
cin inhalation powder group and this was maintained
throughout Cycles 2 and 3.
decreased the sputum density of both non-mucoid and
mucoid phenotypes of P. aeruginosa compared with
placebo at Day 28 of Cycle 1 [mean decrease (SD) 1.91
(2.54) vs. 0.15 (0.68) log10 CFU/g for non-mucoid
phenotype and 2.61 (2.53) vs. 0.43 (1.05) log10CFU/g
for mucoid phenotype, respectively]. After switching
were similar between the two groups in Cycles 2 and 3
with a trend showing P. aeruginosa density increasing
after 28 days off treatment and then decreasing when
on treatment (Fig. 4 presents combined mean of all
The number of patients with MIC values >8mg/ml for
P. aeruginosa at baseline and at the end of Cycle 3 are
shown in Table 2. There was a slightly higher number of
patients with increased MIC values after 2–3 cycles of
tobramycin inhalation powder treatment.
The proportion of patients requiring any additional
antipseudomonal antibiotic in Cycle 1 (including 28 days
TABLE 1—Baseline Demographic and Clinical Characteristics (All Treated Patients)
Tobramycin inhalation powder
13.2 (3.91) Age (years), mean (SD)
Age group, n (%)
?6 to <13 years
?13 to <22 years
Sex, n (%)
Race, n (%)
Body mass index (kg/m2), mean (SD)
FEV1% predicted, mean (SD)a
FEV1% predicted distributiona, n (%)
?25 to <50
?50 to ?80
aExcluding patients from Latin American sites with any potential spirometry quality concerns (TIP, n¼32
and placebo, n¼37); SD, standard deviation; FEV1, forced expiratory volume in 1sec.
Fig. 3. Relative change from baseline (95% CI) in forced
expiratory volume in 1sec (FEV1) % predicted over three cycles
in patients receiving tobramycin inhalation powder (112mg
tobramycin; mITT population). Gray dotted line¼placebo [pla-
cebo for Cycle 1, TIP for Cycles 2 and 3]; black line¼TIP [for all
three cycles]; TIP¼tobramycin inhalation powder.
Fig. 4. Mean Pseudomonas aeruginosa densities of all pheno-
types(mucoid,non-mucoid, and smallcolonyvariant)over three
cycles of treatment in patients receiving tobramycin inhalation
powder (112mg tobramycin; all treated patients). Gray dotted
line¼placebo (placebo for Cycle1, TIP for Cycles 2 and 3); black
line¼TIP (for all three cycles); TIP¼tobramycin inhalation
powder; CFU¼colony forming unit.
234Konstan et al.
on and 28 days off treatment) was lower with tobramycin
inhalation powder than placebo (13.0% vs. 18.4%). In
those patients requiring additional antipseudomonal anti-
biotics, the duration of use over the 56 days of the cycle
was shorter in the tobramycin inhalation powder group
receiving tobramycin inhalation powder were hospital-
12.2% of patients on placebo had respiratory-related
hospitalizations with an average duration of 12.3 days.
Administration time for tobramycin inhalation powder
was approximately 4–6min. Administration of the first
to train patients in the correct use of the T-326 Inhaler.
In Cycle 1, AEs were reported by 75.5% of placebo-
treated versus 50.0% of tobramycin inhalation powder-
treated patients (Table 3). In this cycle, the most common
AEs in the tobramycin inhalation powder group were
cough, lung disorders (generally reported as a pulmonary
or CF exacerbation), and pharyngolaryngeal pain (sore
throat), and in the placebo group were cough, lung
transient. The most common AEs in patients receiving
tobramycin inhalation powder over three cycles (includ-
ing off treatment period) were cough, lung disorders,
pharyngolaryngeal pain, and pyrexia (Table 3). Cough
was most commonly reported by patients receiving
placebo in Cycle 1 and tobramycin inhalation powder in
Cycles 2 and 3. The majority of cough events during the
study were reported as an increase or worsening of cough
above baseline. The frequency of lung disorders in any
cycle appeared to be higher in the tobramycin inhalation
group (21.7% over three cycles of treatment) than in the
placebo group (12.2% over two cycles of treatment),
whereas the incidencewas comparable in Cycle 1 (10.9%
events (SAEs) in Cycle 1 was lower in the tobramycin
were lung disorders (6.5% and 8.2% in the tobramycin
inhalation powder and placebo groups, respectively).
During three cycles of tobramycin inhalation powder
treatment (including the off treatment periods), SAEs
were reported by five patients (10.9%), and during two
cycles of tobramycin inhalation powder treatment in the
placebo group, SAEs were reported by six patients
(14.6%).The mostcommonSAE inboth groupswas lung
disorders (MedDRA coding for reported term lung
exacerbation), occurring in 6.5% of patients in the
tobramycin inhalation powdergroup and 9.8% of patients
during the last two cycles of tobramycin inhalation
powder treatment in the placebo group.
There was one death reported in the study. A placebo-
treated patient took her last treatment on Day 8 during
(pulmonary exacerbation) the next day. Her death due to
decompensated chronic cor pulmonale occurred 39 days
after the last study visit. This patient did not receive any
tobramycin inhalation powder.
Serum tobramycin concentrations were determined
before (trough level) and 60min after (peak level) the
administration of tobramycin inhalation powder. At the
end of Cycle 1, mean?SD trough and peak serum
concentrations were 0.29?0.27 and 1.99?0.59mg/ml,
respectively. At the end of Cycle 2, the levels were
0.38?0.44 and 1.64?0.96mg/ml, respectively. One
patient had a trough tobramycin serum concentration
there was no clinical evidence of nephrotoxicity or
No major changes from baseline to pre-specified time
points or between-treatment differences for biochemical
or hematological measures were observed. No significant
changes in renal function were observed as measured by
TABLE 2—Prevalence of Pseudomonas aeruginosa Phenotypes With a Tobramycin Minimum Inhibitory Concentration
>8mg/ml (All Treated Patients)
Tobramycin inhalation powder
(for all three cycles)
Placebo (placebo one cycle,
tobramycin inhalation powder for two cycles)
No. of patients with
No. patients with
available MIC data
No. of patients with MIC
No. patients with available
End of Cycle 3
End of Cycle 3
MIC, minimum inhibitory concentration.
Tobramycin Inhalation Powder in Cystic Fibrosis 235
increases in blood urea nitrogen, serum creatinine, or
and systolic and diastolic blood pressure were observed.
Six patients experienced a ?20% decrease in FEV1%
bronchospasm): one patient receiving tobramycin inhala-
tion powder (Cycle 1, Day 1), one patient receiving
28), and four patients receiving placebo in Cycle 1 (two
on Day 1 and two on Day 28). Four of these patients
received a bronchodilator prior to receiving study drug.
Audiology was performed at selected sites in 22
patients (13 in tobramycin inhalation powder group and
9 in placebo group). None of the patients reported any
hearing complaints such as tinnitus, ear pressure, or
sensoneural hearing loss at any time during the three
by a conductive audiology test. However, this was
generally transient and not suspected to be drug related
by the study investigators.
Tobramycin inhalation solution 300mg/5ml b.i.d.
administered by nebulization is approved and widely
used for the treatment of P. aeruginosa infection in CF
safety of a new drug-device combination of tobramycin
inhalation powder (112mg tobramycin) delivered by the
T-326 Inhaler. This new formulation in development is
intended to offer the same benefits as TIS (i.e.,
significantly improved lung function, reduced hospital-
izations, and improved quality of life) with the advantage
of greater convenience.
Tobramycin inhalation powder significantly (P¼
0.0016) improved FEV1 % predicted compared with
placebo following 28 days of treatment in Cycle 1
(primary efficacy measure) and improvements were
maintained throughout the study. Tobramycin inhalation
powder also reduced sputum P. aeruginosa density, and
reduced the need for other antipseudomonal antibiotics as
well as the incidence of respiratory-related hospital-
izations compared with placebo. It should be noted that
efficacy boundaries were reached at the interim analysis
and the study was stopped early based on the recom-
mendation of an independent DMC; this new formulation
has demonstrated benefits on key endpoints relevant to its
A single-dose, dose–escalation study showed that the
serum and sputum pharmacokinetic profiles of tobramy-
cin inhalation powder (112mg tobramycin) were similar
to that of TIS (300mg tobramycin/5ml preservative-free
solution).16These data suggest that the efficacy and
safety profile of tobramycin inhalation powder is
expected to be comparable to that of the TIS formulation;
this was further explored in a recently completed study
that directly compared tobramycin inhalation powder
TABLE 3—Most Common Adverse Events (?5% in Any Group) Occurring in Cycle 1 and in Any Cyclea(All Treated Patients)
Cycle 1Any cycle
powder group [Tobramycin
inhalation powder for three
Placebo group [Tobramycin
inhalation powder inhalation
powder for two cyclesb
Any adverse event
Upper respiratory tract infection
Aspartate aminotransferase increased
aEach cycle included 28 days on and 28 days off treatment.
bAdverse events occurring in Cycles 2 and 3 in the placebo group.
cLung disorders were generally reported by the investigator as a pulmonary or cystic fibrosis exacerbation.
236 Konstan et al.
with TIS, the EAGER trial (ClinicalTrials.gov identifier
In our study, tobramycin inhalation powder improved
FEV1 % predicted from the first week of treatment
and lung function remained above baseline values
throughout the study, including the 28-day periods
when tobramycin was not being administered. This is
consistent with data presented by Ramsey et al.9who
showed that TIS 300mg/5ml b.i.d. (28 days on and
during the first 2 weeks of treatment, and improvements
were maintained above pre-treatment values for the
duration of the trial.
Our results show that sputum P. aeruginosa density
decreased by approximately 2 log10CFU/g at the end of
each of the three 28-day tobramycin inhalation powder
treatment periods and values returned towards those at
baseline during periods when the drug was withheld.
Again, these results are consistent with the bactericidal
effects of TIS 300mg/5ml described by Ramsey et al.9In
that study, treatment effect was greatest during the first
two cycles of treatment (average reductions of between
1.8 and 2.2log10CFU/g); however, the magnitude of
bacterial reduction was smaller with the third cycle of
not observed in our study, where reductions in sputum
density of P. aeruginosa were consistent across all three
Exposure of bacteria to antibiotics may alter their
tobramycin inhalation powder-treated patients with an
MIC of >8mg/ml increased slightly following 2–3 cycles
of treatment. However, thresholds of susceptibility to
inhaled therapy as the drugconcentrationsachieved at the
site of infection with inhaled antibiotics can be signifi-
cantly higher than systemic concentrations.16Maximum
tobramycin concentrations in sputum 30min after
single-dose administration of tobramycin inhalation
powder (112mg tobramycin) have been shown to be
1048?1080mg/g.16This exceeds, by several times, the
MIC of tobramycin measured invitro in the vast majority
of isolates from infected CF patients.
Inhaled antibiotics are an attractive option in the
management of chronic lung infection. However, admin-
istration of aerosolized antibiotics such as TIS requires a
PARI-LC1PLUS nebulizer only. Consequently, drug
administration times with the approved TIS formulation
are prolonged (15.8?4.0min, excluding cleaning and
disinfection times).16For patients on multiple therapies,
time taken to administer, clean and disinfect the equip-
ment can be burdensome, and may contribute to poor
outcomes. In our study, total administration times for
tobramycin inhalation powder were 4–6min (as assessed
by the study investigators), which is consistent with
administration times previously reported for this formu-
tolerated in this study. AEs were as expected for this
population and this class of drug. The overall incidence
rates of AEs and SAEs were generally higher in the
placebo group relative to the tobramycin inhalation
to Cycle 1. The incidence of lung disorders was slightly
placebo arm during Cycle 1. However, the incidence
appears to be higher when comparing tobramycin
inhalation powder over three cycles versus placebo for
the last two cycles, when all patients have received
tobramycin inhalation powder. This may be due to the
differing duration of exposure to tobramycin inhalation
powder in the two study arms. Serum tobramycin
concentrations after inhalation of tobramycin inhalation
1 and 2, and in patients who were terminated from the
study early. Serum concentrations were at least sixfold
lower than both the trough levels (>2mg/ml) and
maximum levels (>12mg/ml) recommended for avoid-
ance of toxicity associated with intravenous tobramycin
therapy.23There were no apparent major changes from
baseline to specified time points or between treatment
differences observed for any biochemical, hematology
parameter, and vital signs during the study. Clinically
significant renal function changes as noted by rising
blood urea nitrogen, serum creatinine, and proteinuria
were not reported. None of the patients reported hearing
complaints (tinnitus, ear pressure, or hearing loss) during
the course of the study. In addition, transient hearing loss
was not attributed to tobramycin by the study investi-
gators. There were only two cases of airway reactivity to
tobramycin inhalation powder treatment over the three
treatment cycles (compared with four cases with placebo
in Cycle 1).
In summary, alternate-month administration of tobra-
mycin inhalation powder (112mg tobramycin) b.i.d. was
effective and well tolerated in the treatment of P.
aeruginosa infection in CF patients. Tobramycin inhala-
tion powder improved lung function, decreased sputum P.
aeruginosa density and reduced respiratory-related hos-
pitalizations, and use of other antipseudomonal anti-
approved TIS formulation. The new drug-device combi-
nation for tobramycin inhalation powder could offer an
important alternative for treating CF patients with P.
may have beneficial effects on adherence and clinical
Tobramycin Inhalation Powder in Cystic Fibrosis 237
participating CF centers, the Cystic Fibrosis Foundation
Data Safety Monitoring Board, and the Cystic Fibrosis
Therapeutics Development Network during this study.
Editorial assistance was provided by Melanie Stephens,
ACUMED, UK. This assistance was funded by Novartis
Pharma AG. Dr. Konstan has relationships with Aradigm
Corp, Boehringer Ingelheim, CSL Behring, Genentech,
GlaxoSmithKline, Gilead Sciences, Inc., NanoBio,
Nektar, Novartis Pharmaceuticals, PTC Therapeutics,
Roche, Transave, Inc., and Vertex Pharmaceuticals, Inc.
Dr. Geller has relationships with Bayer, CSL Behring,
Discovery Labs, Genentech, Gilead Sciences, Inc.,
Inspire, MAP Pharmaceuticals, Mpex, NanoBio, Nektar,
Novartis Pharmaceuticals and Philips Respironics. Dr.
Minic ´ declaresnoconflictsofinterest.FlorianBrockhaus,
Jie Zhang, and Gerhild Angyalosi are employees of
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