American Journal of Respiratory and Critical Care Medicine

Rationale: New treatment strategies are needed to improve airway clearance and reduce the morbidity and the time burden associated with cystic fibrosis (CF).

Objectives: To determine whether long-term treatment with inhaled mannitol, an osmotic agent, improves lung function and morbidity.

Methods: Double-blind, randomized, controlled trial of inhaled mannitol, 400 mg twice a day (n = 192, “treated” group) or 50 mg twice a day (n = 126, “control” group) for 26 weeks, followed by 26 weeks of open-label treatment.

Measurements and Main Results: The primary endpoint was absolute change in FEV1 from baseline in treated versus control groups, averaged over the study period. Secondary endpoints included other spirometric measurements, pulmonary exacerbations, and hospitalization. Clinical, microbiologic, and laboratory safety were assessed. The treated group had a mean improvement in FEV1 of 105 ml (8.2% above baseline). The treated group had a relative improvement in FEV1 of 3.75% (P = 0.029) versus the control group. Adverse events and sputum microbiology were similar in both treatment groups. Exacerbation rates were low, but there were fewer in the treated group (hazard ratio, 0.74; 95% confidence interval, 0.42–1.32; P = 0.31), although this was not statistically significant. In the 26-week open-label extension study, FEV1 was maintained in the original treated group, and improved in the original control group to the same degree.

Conclusions: Inhaled mannitol, 400 mg twice a day, resulted in improved lung function over 26 weeks, which was sustained after an additional 26 weeks of treatment. The safety profile was also acceptable, demonstrating the potential role for this chronic therapy for CF.

Clinical trial registered with (NCT 00630812).

Scientific Knowledge on the Subject

Despite recent advances in treatment, patients with cystic fibrosis continue to experience a progressive decline in lung function and premature mortality. Mannitol is a dry powder agent with osmotic properties that hydrates the airway surface and changes mucus rheology, thus aiding mucociliary clearance from the lungs.

What This Study Adds to the Field

This double-blind, randomized Phase III trial demonstrates that adding mannitol to standard therapy produces sustained improvement in lung function for 26–52 weeks. Quantitative microbiology showed added safety.

Cystic fibrosis (CF) lung disease is characterized by reduced hydration of the airway surface liquid and impaired mucociliary clearance. The difficulty in clearing airway secretions and pathogens leads to chronic airway obstruction, inflammation, and infection, with intermittent pulmonary exacerbations and ultimately respiratory failure (1, 2).

There are numerous therapies directed toward the treatment of the lungs to slow the progression of the disease. These treatments include antibiotics, antiinflammatory agents, mucolytics, and agents and maneuvers that enhance airway clearance (35). Current treatment guidelines recommend inhaled dornase alfa (rhDNase, Pulmozyme; Genentech, San Francisco, CA) and inhaled hypertonic saline (an osmotic agent that may help to restore the airway surface liquid) to improve lung function and reduce exacerbations (6).

However, the number of treatments prescribed for patients with CF and the amount of time it takes to accomplish them imposes a significant burden on the patient. There remains a need for effective therapies that can improve mucociliary clearance and decrease the time burden of disease associated with CF. When inhaled, mannitol (a sugar alcohol) is believed to increase surface liquid in the airways by creating an osmotic gradient that encourages movement of water into the lumen, and thereby enhancing mucociliary clearance (7). Mannitol is a dry powder and is inhaled from a simple, disposable, capsule-based dry-powder inhaler (DPI). As such, it has the potential to be a more convenient alternative because it does not require refrigeration, nebulization, equipment cleaning, or sterilization.

In a small, double-blind crossover study in which 39 patients with mild-moderately severe CF inhaled 420 mg of mannitol twice a day and placebo (nonrespirable mannitol; each for 2 wk), the active treatment produced a significantly greater improvement in FEV1 from baseline (8). Sputum samples from the treated group showed improved hydration and surface properties, and that these changes correlated with improvements in airway function (9). A Phase III trial of mannitol in 295 subjects from Europe, Australia, and New Zealand demonstrated that mannitol was effective in improving lung function (10).

The purpose of this second international Phase III study was to determine whether long-term (26 wk) administration of mannitol improves FEV1. FEV1 was used as the primary outcome variable, because it is the strongest clinical predictor of survival in patients with CF (1113).

In addition to extending the understanding of potential benefits for lung function, the study explored the effect of mannitol treatment on the frequency of pulmonary exacerbations, which is known to associate with accelerated loss of lung function and decreased survival (1416). Given a possible influence of mannitol on lung microbiology, quantitative microbiology was explored.

This was a 26-week double-blind, randomized, controlled trial of inhaled mannitol (Pharmaxis, Sydney NSW, Australia), 400 mg twice a day, versus a control of mannitol, 50 mg twice a day, followed by a 26-week open-label extension during which all subjects received active treatment. Low-dose mannitol was chosen as the placebo after discussion with regulatory agencies and in accordance with the results of the dose-finding study (17).

Selection of Patients

The study was conducted in full accordance with the current revision of the Declaration of Helsinki and the Good Clinical Practice: Consolidated Guideline approved by the International Conference on Harmonization. The study was approved by the institutional review board or ethical committee of each participating hospital and written consent was obtained from each patient or their legally authorized representative.

The study was conducted at 53 sites in North America (31), South America (8), and Europe (14). To be eligible, patients had to have a confirmed diagnosis of CF, be at least 6 years of age, and have an FEV1 between 40% and 89% of predicted values (18, 19). Eligible patients were given a mannitol tolerance test (MTT) to exclude those with mannitol-induced bronchospasm. Use of nebulized hypertonic saline during the study was prohibited but all other therapies were continued. Full details of the inclusion–exclusion criteria and the MTT can be found in the online supplement.

Randomization and Masking

Patients were randomized to active treatment or the control arm in a 3:2 ratio. Randomization was stratified by country and use of dornase alfa.

Study Drug

Patients were assigned to receive 10 capsules of inhaled mannitol, 40 mg (mannitol group), or subtherapeutic 5 mg per capsule (control group) twice a day for 26 weeks. Drug was administered by a single-dose dry-powder RS01 inhaler Model 7 (Plastiape, Milan, Italy). Patients had five visits over 26 weeks and a further two visits during the open-label phase to 52 weeks.

Outcome Measures

The primary efficacy endpoint was the between-group difference in the absolute value of FEV1 averaged over the double-blind phase of the study.

Secondary endpoints indicative of pulmonary function included group differences in percent predicted FEV1 at 26 weeks; FVC; and forced expiratory flow, midexpiratory phase. Mannitol had to be withheld for at least 6 hours before spirometry testing as were short-acting bronchodilators. Long-acting bronchodilators were withheld for at least 12 hours. Other secondary endpoints included the number of pulmonary exacerbations meeting the prespecified protocol definition (PDPEs), which included treatment with intravenous antibiotics and presence of specified signs and symptoms (20), hospitalizations, and use of antibiotics for a pulmonary exacerbation. During and for the first 30 minutes after the initial administration of mannitol or control at Visit 1 (Week 0) and Visit 3 (Week 14), sputum weights were measured. The quality of spirometry met the 2005 American Thoracic Society/European Respiratory Society criteria (21). Thus, the FEV1 and FVC used were the best values even if they were from different attempts. Quality of life was assessed using the Cystic Fibrosis Questionnaire-R (22).

Adverse Events

Assessment of adverse events (AEs) included complete blood count, liver and renal function tests, and physical examinations including vital signs, and patients were also asked to record a study diary.


Given a possible influence of mannitol on lung microbiology, sputum samples were collected at the baseline visit and at each of the four visits during the study's double-blind phase. Qualitative sputum microbiology was performed for Staphylococcus aureus and Pseudomonas aeruginosa at baseline and Weeks 6 and 26. Central laboratory facilities for the United States and Canada were provided by Quest Diagnostics, Valencia, California; for Europe by Quest Diagnostics, Middlesex; and for Argentina by Centralab, Buenos Aires.

Statistics and Statistical Methods

The study was designed to have 80% power to detect a change from baseline of 79.3 ml with active treatment. Calculation of total sample size assumed a dropout rate of 30% in the mannitol 400 mg twice a day arm (see online supplement).

Spirometry endpoints were analyzed using mixed model repeated measures methodology and an unstructured variance–covariance structure. Mixed model repeated measures produced an estimate of the difference between mannitol and control patients based on measures repeated at Weeks 6, 14, and 26 (overall treatment effect). Change in percent predicted FEV1 was assessed by analysis of covariance at Week 26. Data on pulmonary exacerbations, hospitalization, and antibiotic use were analyzed by Poisson regression and the rate ratio estimated. Covariates included treatment group; baseline response (for spirometry measures only); disease severity at baseline; age; sex; rhDNase use; country of participation; visit and visit by treatment group interaction term for the mixed model repeated measures models only; and, for pulmonary exacerbations, PDPEs, and hospitalization, prior history of these events.

A single preplanned interim analysis was conducted during the study and the Haybittle-Peto stopping rule was to be used to determine whether the study was to terminate early. As a result of this interim analysis, the primary efficacy endpoint was tested at a 4.98% significance level.

Patient Characteristics

The study was conducted between September 2008 and April 2010. Figure 1 shows that of the 342 potentially eligible patients, 318 (93%) completed and passed the MTT and were randomized, of whom 305 patients began study treatment. Patient demographics are shown in Table 1, and reveal that patients in the two arms of the study were well matched.


CharacteristicMannitol (n = 184)Control (n = 121)
Age, yr
 Median (min, max)18 (6, 48)17 (6,53)
 Children (6–11)19%19.8%
 Adolescents (12–17)30.4%32.2%
rhDNase user74.5%76%
CF mutation ΔF508/ΔF50841.8%37.2%
Pulmonary exacerbations in preceding year, mean (SD)0.73 (1.15)0.61 (0.94)
Hospitalizations in preceding year, mean (SD)0.6 (1.11)0.6 (0.93)
FEV1 at screening
 L, mean (SD)2.06 (0.71)2.02 (0.72)
 % predicted, mean (SD)65.2 (13.9)64.4 (15.3)
FEV1 at baseline
 L, mean (SD)2.06 (0.77)1.96 (0.74)
 % predicted, mean (SD)64.8 (15.7)62.5 (16.0)
BMI kg/m2, mean (SD)20 (4.1)19.8 (3.7)
Use of systemic antibacterials75.5%81%
Use of inhaled antibiotics60.3%57.9%
Drugs for obstructive airway disease
 Salbutamol (albuterol)98.9%99.2%
 Inhaled corticosteroids*51.1%50.4%

Definition of abbreviations: BMI = body mass index; CF = cystic fibrosis; max = maximum; min = minimum; rhDNase = recombinant human deoxyRNase.

*Includes subjects who were on combination of an inhaled corticosteroid and a β agonist.

One important difference between treatment groups was the mean change in FEV1 measures from the screening visit to the baseline visit (Visit 1), which dropped in the control group but remained stable in the mannitol group (Table 1).

Compliance and Completion

At each visit, patients returned all used and unused blister packs of active drug or control. These were reconciled against numbers dispensed. Compliance with protocol treatment was defined as use of 60% or more of drug dispensed. By this criterion, compliance was good in both arms: mean 85.2% (SD, 23.81%) of mannitol patients and 88.7% (SD, 17.66%) of control subjects.

Among the safety and intent-to-treat population of 305 in total (mannitol 184 and control subjects 121), 260 (mannitol 153 and control subjects 107) completed the 26 weeks of double-blind treatment. The main reason for discontinuation was withdrawal of consent (13 mannitol patients and 7 control subjects). Lack of time was the most common reason cited. Thirteen subjects in the mannitol group and five in the control group discontinued the study because of AEs, with increased cough being the most frequently cited event.

Change in FEV1 and FEV1 percent predicted.

The mean improvement in FEV1 was greater in the mannitol group than the control group (106.5 vs. 52.4 ml; P = 0.059) (Table 2) (Figure 2A). The relative change from baseline FEV1 (milliliters) in the mannitol group was 8.22%, whereas that in the control group was 4.47% (effect between groups 3.75%; P = 0.029). There was a difference in the secondary endpoint of absolute FEV1 percent predicted (2.42% FEV1; P = 0.024) at 26 weeks. Relative percent change in FEV1 (percent predicted) over the study was greater in the mannitol group than in the control group (3.59%; P = 0.033) (Figure 2B).


EndpointMannitol (n = 184)Control (n = 121)Treatment Effect
Absolute increase in FEV1 (ml) from baseline (Visit 1)
 95% CI62.4 to 150.62.1 to 102.7−2 to 110.3
P vs. baseline<0.0010.04
P mannitol vs. control0.059
Absolute increase in FEV1 (ml) from adjusted baseline (taken as mean of screening and Visit 1)*
 95% CI67.8 to 149.5−9.1 to 84.219.1 to 123.1
P vs. baseline<0.0010.114
P mannitol vs. control0.008
Relative % change in FEV1 (ml) from baseline*
 95% CI5.57 to 10.881.44 to 7.500.38 to 7.12
P vs. baseline<0.0010.004
P mannitol vs. control0.029
Relative % change in FEV1 (% predicted) from baseline*
 95% CI4.12 to 9.330.16 to 6.100.29 to 6.90
P vs. baseline<0.0010.039
P mannitol vs. control0.033
At Week 26 absolute increase in % predicted FEV1+
 95% CI1.49 to 4.78−1.18 to 2.620.33 to 4.51
P vs. baseline<0.0010.458
P mannitol vs. control0.024

Definition of abbreviation: CI = confidence interval.

*Post hoc analysis.

Analysis of covariance analysis: prespecified secondary endpoint for percent predicted FEV1 at Week 26.

Prior clinical intervention studies have used an average FEV1 over two or more visits to establish a baseline from which to measure change, as opposed to a single visit (20). Therefore, in a post hoc sensitivity analysis, baseline FEV1 was calculated as the mean of the values at screening and at Visit 1 (rather than taking the Visit 1 value alone). Using these baseline-corrected values, the overall increase in absolute FEV1 seen in the mannitol group was significantly greater than that in the control group (difference 71.1 ml; P = 0.008). A post hoc examination of the relative change in FEV1 (percent) using the mean of the screening and baseline FEV1 (milliliters) value showed an overall treatment effect that favored the mannitol group (difference 3.97%; P = 0.008).


In the mannitol group, FVC increased 136.3 ml compared with a 65-ml increase in the control group. There was an overall increase of 71.4 ml in FVC in the mannitol group compared with the control group (P = 0.022) (Figure 2C).

Pulmonary Exacerbations, Hospitalization, and Other Outcomes

Over the 26-week period of double-blind treatment, patients in the mannitol group experienced fewer pulmonary exacerbations whether protocol-defined (PDPE) or from any cause (Table 3), but the difference was not statistically significant. Similar numbers of patients were treated with intravenous antibiotics for a PDPE in the mannitol (15.2%) and control (19%) groups. Of these acute exacerbations, most were hospitalized (12% and 15.7%, respectively). The duration of hospital stay was 3 days shorter in patients in the mannitol group. There was no significant difference in quality of life from baseline for either treatment group or between treatment groups for any of the quality of life domains. At Visit 1, patients in the Bronchitol group cleared more sputum during and for 30 minutes post-Bronchitol administration than patients in the control group. The median sputum weights were 2.7 versus 1.7 g, respectively (P = 0.04). At Week 14, patients in the Bronchitol group cleared less sputum than at Visit 1, but still more than the control group. Median weights were 2 versus 1.5 g, respectively (P = 0.26).


Mannitol (n = 184)Control (n = 121)Reduction in Annualized Rate*P Value
Proportion of patients with one PDPE during 26 wk of double-blind treatment15.2%19%
PDPE rate ratio (95% CI)0.85 (0.51–1.41)15%0.520
 PDPE hazard ratio (95% CI)0.74 (0.42–1.32)0.308
Patients hospitalized because of PDPE12%15.7%
 PDPE hospitalization rate ratio (95% CI)0.75 (0.42–1.33)25%0.328
 Mean duration of hospital stay for PDPE, d12.0915.42
SD 7.91SD 10.16

Definition of abbreviations: CI = confidence interval; PDPE = protocol-defined pulmonary exacerbation.

*Adjusted for prespecified covariates including pulmonary exacerbation history.

Cox proportional.

Only includes those subjects who were hospitalized.

Adverse Events

The proportion of patients reporting AEs was similar in the mannitol and control groups (89.7% and 87.6% of patients, respectively). The incidence of severe AEs was similar in the two arms of the study, occurring in 29 (15.8%) of the mannitol group and in 19 (15.7%) of the control group. Serious treatment-related AEs occurred in 2.2% and 2.5%, respectively. The proportion of patients with treatment-related AEs leading to withdrawal of treatment was 6.5% compared with 1.7%, respectively (Table 4). Condition aggravated (i.e., acute pulmonary exacerbation) was the most frequently reported AE (mannitol 41.3% and control 44.6%). Headache was reported by 14.1% of mannitol subjects and 18.2% of control subjects, whereas 15.2% of mannitol subjects experienced cough (control 13.2%). Hemoptysis reported as either an AE or as part of an exacerbation was similar in the treatment arms at 11.4% versus 10.7% in the mannitol and control groups, respectively.


Category of AEMannitol (n = 184)Control (n = 121)
One or more AE89.7%87.6%
TEAEs by MedDRA preferred term (occurring in 5% patients overall)
 Condition aggravated41.3%44.6%
 Pharyngolaryngeal pain10.3%10.7%
 Abdominal pain7.6%6.6%
 Upper respiratory tract infection5.4%9.1%
Severe AE15.8%15.7%
AE leading to discontinuation from study7.1%4.1%
Treatment-related AE leading to discontinuation from study6.5%1.7%
Treatment-related serious AE2.2%2.5%

Definition of abbreviations: AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent adverse event.

*When using hemoptysis symptoms reported as part of a protocol-defined pulmonary exacerbation the incidence was 11% and 11.6%, respectively.

There was one death in the study population: a patient in the control group died approximately 3 months after discontinuing study treatment because of a serious AE (pneumothorax). The death was considered unrelated to treatment.

Clinically significant findings regarding vital signs, the physical examination, hematology, and biochemistry were generally similar in the two treatment groups and related to the underlying disease. Abnormal white cell count was the most common hematologic abnormality, and was seen in five patients from each treatment group. There were no significant findings for liver function enzymes or diabetes control.


There were no qualitative changes in microbiology results from baseline in either group. Mannitol and control groups showed no change from baseline to Week 26 in the frequency of sputum colonization by S. aureus or P. aeruginosa. There was no change in the number of colony-forming units per gram sputum. Data are given in Tables 5–7.


Pseudomonas aeruginosaMannitol (n = 184)Control (n = 121)
Baselinen = 106n = 68
 Percent of patients with pathogen present48.152.9
 Mean (SD) log CFU/g6.9 (1.6)6.1 (1.9)
Week 26n = 82n = 67
 Percent of patients with pathogen present41.558.2
 Mean (SD) log CFU/g6.4 (1.7)6.3 (2)


Staphylococcus aureusMannitol (n = 184)Control (n = 121)
Baselinen = 112n = 76
 Percent of patients with pathogen present64.373.7
 Mean (SD) log CFU/g6.8 (1.6)6.1 (1.7)
Week 26n = 93n = 70
 Percent of patients with pathogen present62.462.9
 Mean (SD) log CFU/g6.7 (1.5)6.7 (1.4)


OrganismMannitol (n = 184) n (%)Control (n = 121) n (%)
Visit 1 (baseline)n = 184n = 121
 Any organism165 (89.7)105 (86.8)
Pseudomonas aeruginosa (mucoid)49 (26.6)35 (28.9)
Pseudomonas aeruginosa (nonmucoid)52 (28.3)33 (27.3)
Pseudomonas spp (other)8 (4.3)3 (2.5)
Staphylococcus aureus84 (45.7)55 (45.5)
 Methicillin-resistant Staphylococcus aureus19 (10.3)12 (9.9)
Burkholderia cepacia (cenocepacia)5 (2.7)8 (6.6)
Aspergillus spp21 (11.4)13 (10.7)
Visit 4 (Week 26)n = 153n = 110
 Any organism137 (89.5)100 (90.9)
Pseudomonas aeruginosa (mucoid)44 (28.8)36 (32.7)
Pseudomonas aeruginosa (nonmucoid)26 (17)30 (27.3)
Pseudomonas spp (other)3 (2)1 (0.9)
Staphylococcus aureus75 (49)55 (50)
 Methicillin-resistant Staphylococcus aureus18 (11.8)11 (10)
Burkholderia cepacia (cenocepacia)5 (3.3)8 (7.3)
Aspergillus spp19 (12.4)22 (20)
Open-Label Phase

A total of 260 patients completed the double-blind phase (153 mannitol and 107 control) and all entered the open-label phase of the study. Of these, 242 patients completed the open-label phase including 143 mannitol (93.4% who started) and 99 control subjects (92.5% who started). Ten patients (5.4%) from the mannitol group and eight patients (6.6%) from the control group withdrew during the open-label phase. Withdrawals caused by treatment-related AEs were low (one patient from the original mannitol group and three patients from the original control group), whereas overall AEs in the open-label phase were similar between the groups. Eight patients experienced serious treatment-related AEs (mannitol 2.6% and control 3.7%).

For those patients originally randomized to the mannitol group, the increase in FEV1 was maintained for the 12 months of the study, with a mean increase in FEV1 of 87.2 ml or an 8.2% relative change compared with baseline (P = 0.001). Those patients who were initially randomized to the control group during the double-blind phase and then went on to receive mannitol, 400 mg twice daily, in the 6-month open-label phase had a mean FEV1 improvement from baseline of 84 ml (6.3%; P = 0.031) at the end of the open-label phase.

We demonstrated a 105-ml mean improvement in the FEV1 of the mannitol-treatment group, an 8.2% improvement from baseline. However, for the primary endpoint for the study (i.e., the difference in absolute FEV1 between the treated and control groups over 26 wk of the study), statistical significance was narrowly missed (although was significant by relative difference).

We believe that this endpoint was not reached for several reasons. Importantly, analysis of the baseline FEV1 was taken from only one data point (baseline visit) and was not a priori averaged with the screening visit value. Other Phase III CF studies (20) have averaged more than one FEV1 to establish a stable baseline for comparison. The absolute difference in milliliters was significant when a post hoc analysis accounted for the observed baseline variability that was limited to control patients.

A second point is that the control arm received a lower dose of the same drug. It was believed that 50 mg would not be clinically effective because of results from the dose-escalation study (17) where 40-mg dose seemed to have no effect on FEV1. However, it is possible that the lower dose of mannitol may have some benefit, but not as much efficacy as the higher dose, and this finding emerged because of the larger number of patients in this study. The improvement in FEV1 at the lower dose of mannitol (50 mg) does seem to contribute to the lack of statistically significant absolute (milliliter) difference between the two doses of mannitol.

As for the other spirometric measures (percent predicted FEV1 and FVC), the 400-mg inhaled mannitol dose resulted in a statistically and clinically significant average improvement in lung function over the treatment period compared with control.

There were fewer pulmonary exacerbations in the mannitol group, although this did not reach statistical significance. This study was not powered to observe an effect on acute pulmonary exacerbations because they can be relatively uncommon in the course of 6 months. Prior multicenter trials have sometimes detected a decrease in the number of acute pulmonary exacerbations or a delay to the next pulmonary exacerbation (20, 23). However, in this study all preventative medications against acute exacerbations were continued, and thus we believe that it would be difficult to detect change in acute exacerbations in this study over 6 months. Overall there was a low rate of acute exacerbations (<1 per year) in the study population and this was a heavily treated group on many chronic medications. Moreover, we designed this study using a stringent definition of acute pulmonary exacerbation with the use of intravenous antibiotics (20), rather than other definitions that have been developed since the start of the trial (24). Interestingly, patients with a higher rate of pulmonary exacerbation in the year preceding the study were more likely to experience a pulmonary exacerbation during the trial, and the historical rate of pulmonary exacerbations in the year before treatment was 19.7% higher among mannitol than among control patients.

Mannitol was well tolerated, and the proportion of patients discontinuing from the study because of AEs was similar between the groups. The AEs reported were generally mild or moderate and consistent with CF and its treatment. Cough was more common in the mannitol than in the control arm and is a known side effect of this agent. When it contributes to clearance of mucus, cough can be a positive event. However, a small proportion of patients are unable to tolerate it, and cough was the most common treatment-related AE leading to withdrawal. The incidence of severe AEs and serious treatment-related AEs were similar in the two arms of the study. No safety signals of concern were detected.

Hemoptysis is frequently associated with CF exacerbation and therefore many occurrences of hemoptysis were captured as symptoms of pulmonary exacerbation or PDPE but not necessarily as AEs. When hemoptysis reported as a symptom of a pulmonary exacerbation was included in the analysis of hemoptysis AEs, the frequency of hemoptysis was similar overall in the mannitol and control groups. Inhaled mannitol-like hypertonic saline is known to induce bronchospasm in other patient populations. To reduce any potential risk of bronchospasm, a test dose of mannitol was instituted at screening (MTT), and bronchodilator was routinely used before inhaled mannitol administration in the study. A small minority of the CF population (6.4%) did not proceed into the study on initial testing because of bronchial hyperresponsiveness. There was no bronchospasm reported with inhaled mannitol during the study and, surprisingly perhaps, this compares favorably with existing therapies that do not mandate screening or predose bronchodilator use, yet may cause bronchoconstriction. Furthermore, unlike antibiotics that carry a potential for anaphylaxis, bronchospasm after bronchial hyperreactivity is short lived and responsive to bronchodilator.

Mannitol treatment was not associated with an increase in the isolation of S. aureus, P. aeruginosa, Burkholderia cepacia, Stenotrophomonas maltophilia, other gram-negative aerobic organisms, methicillin-resistant S. aureus, small-colony variant, or other pathogens commonly seen in patients with CF. This is a reassuring finding because many organisms are able to use mannitol as a carbon source.

Interestingly, a recent study exploring the aminoglycoside gentamicin in combination with mannitol demonstrated that mannitol and gentamicin could potentiate the eradication of gram-negative bacterial persisters and biofilms, suggesting mannitol might potentially be beneficial in clearing organisms (25).

Inhaled mannitol has other advantages that may reduce the treatment burden for patients. The simple DPI is small, portable, and fairly easy to use, especially in a population of patients who are experienced with inhaled therapies. Each dose takes an average of 5 minutes to administer (data not shown), and it requires no power source other than the patient's inspiratory effort. Another favorable feature of the formulation is that the DPI (unlike a nebulizer) does not require thorough cleaning and disinfection after each use. We speculate that in patients with adequate inspiratory flow and lung volume to successfully actuate the DPI, patients will have more flexibility and may be more adherent with this therapy.

To summarize, in this Phase III study, 12-month use of inhaled mannitol, 400 mg twice a day, resulted in sustained improvement in lung function relative to control, as measured by FEV1 and FVC and reduced exacerbations, and had a good safety profile with excellent treatment compliance over 26 weeks of treatment. Although this study and the earlier Phase III study (10) were statistically significant for change in FEV1 by relative percent predicted, this study did not reach statistical significance for absolute change in milliliters (P = 0.059). The efficacy of inhaled mannitol was demonstrated on top of a background of typical concomitant therapy, such as rhDNase and inhaled antibiotics, perhaps reflecting its different mechanism of action. These results support the use of mannitol as an osmotic, inhalation dry-powder treatment for the daily management of patients with CF to improve overall pulmonary function with a shortened time of treatment burden.

The authors thank the patients and their families who participated in this study and the investigators and study coordinators for each study site. The authors also thank the Cystic Fibrosis Foundation Therapeutic Development Network for their thorough review of the protocol.

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Correspondence and requests for reprints should be addressed to Moira L. Aitken, M.D., University of Washington, Pulmonary and Critical Care Medicine, Box 356522, 1959 Pacific, Seattle, WA 98195-6522. E-mail:

*A complete list of members may be found before the beginning of the references.

Supported by Pharmaxis Limited. The study sponsor participated in the study design, data collection, data analysis, data interpretation, and writing of the report. After completion of the trial, the data were held and analyzed by the sponsor. The corresponding author had full access to all data and has final responsibility for publication.

Author Contributions: All authors helped to interpret data and write the manuscript, and have seen and approved the final version. M.L.A. was the Global Principal Investigator for CF302. M.L.A., P.A.F., D.E.G., A.L., and J.B.Z. were on the CF302 Steering Committee. G.B. was Lead Regional Investigator for France. K.D.B. was Lead Regional Investigator for Belgium. E.G.H. was Lead Regional Investigator for The Netherlands. H.U.H. was Lead Regional Investigator for Germany. H.G.F. approved the statistical plans and assisted the design of CF302. B.C. designed the CF302 study, approved the statistical plans, and was the Sponsor's Responsible Medical Officer. I.M.S. wrote the statistical plans and was responsible for the data analyses.

This article has an online supplement, which is accessible from this issue's table of contents at

Originally Published in Press as DOI: 10.1164/rccm.201109-1666OC on December 23, 2011

Author disclosures

CF302 Investigators: Argentina: Maria Eugenia Alais, Angel Jose Bonina, Juan Carlos Ditondo, Eduardo Lentini, Ines Marques, Ricardo Pinero, Edgardo Segal, and Alejandro Teper. Canada: Brian Lyttle, Roger Michael, and Harvey Rabin. Belgium: Georges Casimir, Christiane DeBoeck, Kristine Deseger, and Anne Malfroot. France: Gabriel Bellon, Francois Bremont, Valerie David, Jean-Christophe Dubus, Isabelle Durieu, Pierre Foucaud, Romain Kessler, Sylvie Leroy, Christophe Marguet, Anne Munck, Dominique Turck, and Laurence Weiss. Germany: Rainald Fischer, Helge Hebestreit, Lutz Nahrlich, and Joachim Reithmuller. The Netherlands: Eric Haarman and Petrus Merkus. United States: Moira Aitken, Bruce Barnett, Drucy Borowitz, Cori Daines, Mark Dovey, Patrick Flume, Peter Fornos, Deborah Froh, David Geller, Manu Jain, Kimberly Jones, Peter Konig, Allen Lapey, Craig Lapin, Bennie McWilliams, Keith Meyer, Peter Murphy, Christopher Oermann, James Royall, Elizabeth Rulon, Matthias Salathe, David Schaeffer, Robert Schoumacher, James Wallace, Donna Beth Willey-Courand, Ronald Williams, Pamela Zeitlin, and Jonathan Zuckerman.


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