Effective Pseudomonas aeruginosa treatment
for patients with cystic fibrosis (CF)1,2

Colobreathe® shows comparable efficacy to nebulised tobramycin in Phase III non-inferiority study1

The Freedom Study

The Freedom study was a prospective, randomised, non-inferiority, Phase III, open-label study designed to compare the efficacy and safety of Colobreathe^® to tobramycin in 380 patients with CF (clinically stable, aged ≥ 6 years with chronic Pseudomonas aeruginosa lung infection, and FEV₁ predicted of 25–75%).

Patients were randomly assigned to receive continuous treatment over a 24-week period with Colobreathe^® DPI (one capsule of 1,662,500 IU twice daily) or to three 28-day, on-off courses of tobramycin nebuliser solution for inhalation (TNSI; 300 mg/5ml twice daily) using a PARI LC Plus nebuliser. Prior to randomisation, all patients received at least two 28-day TNSI on-off cycles.

The primary endpoint was the change in mean FEV₁ predicted from baseline at week 24.

Further Study Design Information

Freedom study design

Primary endpoint:

Change in mean FEV₁ predicted from baseline at week 24.

Secondary endpoints:

Antibiotic susceptibility of Pseudomonas aeruginosa to colistin and tobramycin; Quality of Life CFQ-R; change in FVC, absolute FEV₁ and FEF_25-75; compliance to study medication; adverse events; patient view of trial treatment including time to administer, ease of use and convenience; patient preference.

*Of the patients in the Colobreathe^® arm, 32 withdrew (adverse events=18; lack of efficacy= 2; patient request=9; protocol violation=1; other=2) and one patient dropped out immediately following randomisation and did not receive treatment. †Of the patients in the TNSI arm, 21 withdrew (adverse events=3; lack of efficacy=1; patient request=11; protocol violation=2; other=4).

Primary Endpoint:
Freedom results: Colobreathe® demonstrated non-inferiority to inhaled
tobramycin at 24 weeks in maintenance of lung function1

The adjusted mean difference between the groups in the change in FEV₁ predicted at week 24 was -0.98% (95% CI -2.74% to 0.86% (ITT LOCF))¹
The lower limit of the 95% CI (−2.71%, for patients who completed the study) was within the predefined 3% margin for treatment difference¹

Freedom results: Significantly more patients rated Colobreathe® as
‘very easy’ or ‘easy’ to use vs. nebulised tobramycin (p<0.001)

65.6% of patients indicated a preference for Colobreathe^® over TNSI, with significantly more (90.7%) rating it ‘very easy’ or ‘easy’ to use compared to TNSI (53.9%, p<0.001).

Percentage of Freedom participants rating medication regimen as ‘very easy’ or ‘easy’ to use

Colobreathe®

90.7%

(n=183)

TNSI

53.9%

(n=191)

Safety and tolerability

Colobreathe® was generally well tolerated in the Freedom study

The number of AEs was similar for both groups
- There was a higher incidence of cough, throat irritation and dysgeusia in the Colobreathe^® group compared with the TNSI group
- The incidence of treatment-related AEs was higher in the Colobreathe^® group vs the TNSI group (153/186 patients, 82.3% compared with 90/193, 46.6%), and discontinuations where the primary cause was an AE were also higher in the Colobreathe^® group (18/186 patients, 9.7%, compared with 3/193, 1.6%)
- SAEs were higher in the TNSI group (6.2% of patients vs 4.3% for Colobreathe^®)
Most AEs were mild to moderate in intensity and diminished as patients continued with treatment
There were two deaths in the TNSI group (LRTI related to underlying CF in both patients, additionally arterial thrombosis and multiorgan failure in one), both of which were thought to be unrelated to study medication

	Colobreathe^® (n=186)*	TNSI (n=193)	Total (n=379)
Total number of adverse events	1232	1194	2426
Cough	193 (15.7)	123 (10.3)	316 (13.0)
Dysgeusia	132 (10.7)	62 (5.2)	194 (8.0)
Dyspnoea	81 (6.6)	98 (8.2)	179 (7.4)
Lower respiratory tract infection	79 (6.4)	85 (7.1)	164 (6.8)
Throat irritation	94 (7.6)	63 (5.3)	157 (6.5)
Productive cough	62 (5.0)	76 (6.4)	138 (5.7)

*One patient was randomised but received no treatment.¹

Table adapted from Schuster et al 2013¹

Summary of Colobreathe® safety profile

The most frequently reported adverse events associated with Colobreathe^® are summarised in the table below.*²

  
      System Organ Class
      Very Common (≥ 1/10)
      Common (≥ 1/100 to <1/10)
    
      Nervous system disorders
      
      Balance disorder, headache
    
      Ear and labyrinth disorders
      
      Tinnitus
    
      Respiratory, thoracic and mediastinal disorders
      Dyspnoea, cough, dysphonia, throat irritation
      Haemoptysis, bronchospasm, asthma, wheezing, chest discomfort, lower respiratory tract infection, productive cough, crackles lung
    
      Gastrointestinal disorders
      Dysgeusia
      Vomiting, nausea
    
      Musculoskeletal and connective tissue disorders
      
      Arthralgia
    
      General disorders and administration site conditions
      
      Pyrexia, asthenia, fatigue
    
      Investigations
      
      Forced expiratory volume decreased

System Organ Class	Very Common (≥ 1/10)	Common (≥ 1/100 to <1/10)
Nervous system disorders		Balance disorder, headache
Ear and labyrinth disorders		Tinnitus
Respiratory, thoracic and mediastinal disorders	Dyspnoea, cough, dysphonia, throat irritation	Haemoptysis, bronchospasm, asthma, wheezing, chest discomfort, lower respiratory tract infection, productive cough, crackles lung
Gastrointestinal disorders	Dysgeusia	Vomiting, nausea
Musculoskeletal and connective tissue disorders		Arthralgia
General disorders and administration site conditions		Pyrexia, asthenia, fatigue
Investigations		Forced expiratory volume decreased

For full list of adverse events consult the Summary of Product Characteristics.

*The safety of Colobreathe^® was assessed in a 24-week clinical study in a total of 237 subjects (225 CF patients and 12 healthy volunteers). In the 24-week clinical study, where Colobreathe^® was administered twice daily to adults and children aged 6-17, the adverse reactions identified in the paediatric population were similar to that for the overall population. The most commonly reported adverse reactions as a percent of Colobreathe^® treated paediatric patients were: cough (55%), unpleasant taste (51%), throat irritation (34%), dyspnoea (10%) and dysphonia (10%).²

Further Safety Information

  
        Contraindications
      
      Colobreathe® should not be used in patients with hypersensitivity to the active substance, colistin sulphate or polymyxin B.

Contraindications
Colobreathe^® should not be used in patients with hypersensitivity to the active substance, colistin sulphate or polymyxin B.

  
      
        Special warnings and precautions
      
    

  
      Bronchospasm and coughing
      Bronchospasm or coughing may occur on inhalation. These reactions usually disappear or significantly
diminish with continued use and may be ameliorated by appropriate treatment with beta2-agonists
prior to or following dry powder colistimethate sodium inhalation. If bronchospasm or coughing remain
problematic, withdrawal of treatment should be considered.
    

      Haemoptysis
      Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. The use of colistimethate
sodium in patients with clinically significant haemoptysis should be undertaken or continued only if the
benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.
    

      Acute respiratory exacerbation
      If acute respiratory exacerbations develop additional intravenous or oral antibacterial agent therapy
should be considered.
    

      Oral fungal super-infection
      After each inhalation of Colobreathe®, the mouth should be rinsed with water. The rinse should not be
swallowed. Rinsing may reduce the risk of developing oral fungal super-infection during treatment and
may also reduce the unpleasant taste associated with colistimethate sodium.
    

      Nephrotoxicity/ neurotoxicity
      There is very low transpulmonary absorption of colistimethate after inhalation of Colobreathe®. Care
should still be taken in administering Colobreathe® to patients who are known to have a propensity
for nephrotoxic or neurotoxic events. Caution should be taken with concomitant use of Colobreathe®
and parenteral or nebulised colistimethate sodium. Caution should be taken with concomitant use
of colistimethate sodium and potential nephrotoxic or neurotoxic medicinal products, including nondepolarising
muscle relaxants.
    

      Other
      Colobreathe® should be used with extreme caution in patients with myasthenia gravis because of
potential for drug induced neuromuscular blockade. Colistimethate sodium should be used with extreme
caution in patients with porphyria. Safety and efficacy have been assessed in controlled studies for up to
24 weeks. This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say
essentially ‘sodium-free’.
    

Special warnings and precautions
Bronchospasm and coughing	Bronchospasm or coughing may occur on inhalation. These reactions usually disappear or significantly diminish with continued use and may be ameliorated by appropriate treatment with beta₂-agonists prior to or following dry powder colistimethate sodium inhalation. If bronchospasm or coughing remain problematic, withdrawal of treatment should be considered.
Haemoptysis	Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. The use of colistimethate sodium in patients with clinically significant haemoptysis should be undertaken or continued only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.
Acute respiratory exacerbation	If acute respiratory exacerbations develop additional intravenous or oral antibacterial agent therapy should be considered.
Oral fungal super-infection	After each inhalation of Colobreathe^®, the mouth should be rinsed with water. The rinse should not be swallowed. Rinsing may reduce the risk of developing oral fungal super-infection during treatment and may also reduce the unpleasant taste associated with colistimethate sodium.
Nephrotoxicity/ neurotoxicity	There is very low transpulmonary absorption of colistimethate after inhalation of Colobreathe^®. Care should still be taken in administering Colobreathe^® to patients who are known to have a propensity for nephrotoxic or neurotoxic events. Caution should be taken with concomitant use of Colobreathe^® and parenteral or nebulised colistimethate sodium. Caution should be taken with concomitant use of colistimethate sodium and potential nephrotoxic or neurotoxic medicinal products, including nondepolarising muscle relaxants.
Other	Colobreathe^® should be used with extreme caution in patients with myasthenia gravis because of potential for drug induced neuromuscular blockade. Colistimethate sodium should be used with extreme caution in patients with porphyria. Safety and efficacy have been assessed in controlled studies for up to 24 weeks. This medicinal product contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially ‘sodium-free’.

For full information on contraindications, warnings and precautions please consult the Summary of Product Characteristics.

AEs, adverse events; CDPI, Colobreathe^® dry powder inhaler; CF, cystic fibrosis; CFQ-R, Cystic fibrosis questionnaire- Revised; CI, confidence interval; DPI, dry powder inhaler; FEF_25-75, change in forced expiratory flow between 25% and 75% of the vital capacity; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; ITT, intention to treat; ITT LOCF, intention-to-treat last observation carried forward; IU, international unit; LRTI, lower respiratory tract infection; SAEs, serious adverse events; TNSI, tobramycin nebuliser solution for inhalation.

References:
1. Schuster A, Haliburn C, Döring G, et al. Thorax. 2013;68:344–350.
2. Colobreathe^® Summary of Product Characteristics. Available here.

Effective Pseudomonas aeruginosa treatment for patients with cystic fibrosis (CF)1,2