National Horizon Scanning Centre. Mannitol dry powder for inhalation (Bronchitol) for cystic fibrosis. April 2008

Transcription

1 Mannitol dry powder for inhalation (Bronchitol) for cystic fibrosis April 2008 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The Research Programme is part of the National Institute for Health Research

2 Mannitol dry powder for inhalation (Bronchitol) for cystic fibrosis Target group Cystic fibrosis (CF) - at risk for bronchiectasis. Technology description Mannitol dry powder for inhalation (Bronchitol) is a mucoactive agent that acts by inducing an influx of water into the airway lumen improving hydration of airway secretions, and increasing mucociliary clearance by reducing its viscosity and stimulating cough 1. Mannitol dry powder is administered at 400mg twice daily by inhalation with a hand-held, breath activated device. The company state that initially mannitol dry powder will be add-on therapy to improve lung function and prevent exacerbations. Mannitol dry powder is also in phase III development for the treatment of bronchiectasis and phase II development for the treatment of chronic obstructive pulmonary disease. Mannitol dry powder for inhalation is already approved as a bronchial challenge test (Osmohale) in the UK for identifying bronchial hyperresponsiveness in people with baseline FEV1 of 70% or more. Innovation and/or advantages Mannitol dry powder is a new mucolytic therapy for CF. Dry powder formulation rather than nebulised formulation may be easier and more convenient to use. Developer Pharmaxis Availability, launch or marketing dates, and licensing plans: Mannitol dry powder is in phase III clinical trials. Inhaled mannitol has been granted orphan drug status in both the USA and Europe for the treatment of CF. NHS or Government priority area: This topic is relevant to: The National Service Framework for Children, Young People and Maternity Services (2004). The National Screening Programmes: National Screening Committee policy cystic fibrosis screening (2006). Relevant guidance National Screening Committee. National Screening Committee policy cystic fibrosis screening (in pregnancy) National Screening Committee. National Screening Committee policy cystic fibrosis screening (neonatal) Association of Chartered Physiotherapists in Cystic Fibrosis. Clinical guidelines for the physiotherapy management of cystic fibrosis The Cystic Fibrosis Trust s Clinical Standards and Accreditation Group. Standards for the clinical care of children and adults with cystic fibrosis in the UK

3 Clinical need and burden of disease CF is the most common life-limiting, autosomal recessively inherited disease in caucasian populations, with a carrier frequency of 1 in 25 and incidence of 1 in 2,500 live births 5. Based on this incidence there were approximately 270 babies born in 2006 with CF in England and Wales, and it is estimated that CF affects over 8,000 people in the UK. Although CF is a progressive condition it has an improving prognosis leading to a rapidly increasing number of adult patients with inevitably more severe problems. In 2005/06 more than half of the UK population with CF were older than 16 years of age. In 2005/06, there were over 5,000 in-patient episodes of CF with pulmonary manifestations (E840) accounting for 36,600 bed days. Most of the morbidity and mortality is from pulmonary disease, which is characterised by bronchial and bronchiolar obstruction with thick tenacious secretions that are difficult to clear and repeated infections and progressive lung destruction 1. In 2005, 97 deaths from CF were recorded in England and Wales, 56 of those with pulmonary manifestations. In 2004/05, palliative care statistics for children and young adults shows 5,400 finished consultant episodes and over 10.5 M expenditure on patients with CF 6. Existing comparators and treatments Airways clearance therapy. Inhaled pulmonary therapy: Bronchodilators: short acting and long acting inhaled beta-2 agonist. Inhaled corticosteroids. Inhaled mucolytics: recombinant human deoxyribonuclease. Nebulised hypertonic saline. Antibiotics. Efficacy and safety A pilot study shows the utility of osmotic agents, such as mannitol and hypertonic saline, in improving bronchial mucus clearance in patients with CF. In general, both substances were equally efficacious and well-tolerated 7. Trial name or NCT ; phase II code Sponsor Pharmaxis Status Completed Location Australia, New Zealand Design Randomised, double-blind, placebo control, crossover assignment Participants n=39; >8 years; cystic fibrosis; FEV1 between 40% and 80%. mannitol 420mg or placebo. Follow-up 8 weeks Primary FEV1 outcome Secondary Other measures of lung function; sputum microbiology; sputum rheology; quality of outcomes life (QoL); safety. Key results FEV1: increased 7±2% (p<0.01 vs. control) FEV25-75: increased 15.5±5% (p<0.01 vs. control) FEV1/FVC: ratio increase by 2.2±1.1% (p<0.05 vs. control) FVC: increase 4.6±1.6% (not significant) Symptoms: improved (p<0.05 vs. control) Abnormal chest sounds improved (p<0.05 vs. control) 3

4 Adverse effects QoL: improved (not significant) None reported Trial name or NCT ; phase II NCT ; phase NCT ; phase II code III Sponsor Pharmaxis Pharmaxis Pharmaxis Status Ongoing Ongoing Ongoing Location Argentina, Canada Australia, Ireland, United United Kingdom Kingdom Design Randomised, open label, dose comparison, crossover assignment Randomised, doubleblind, placebo control, parallel assignment Randomised, open label, uncontrolled, crossover assignment Participants n=42; >7 years; cystic fibrosis; FEV1 between 40% and 90%. mannitol 40mg, 120mg, 240mg or 400mg. n=340; >6 years; cystic fibrosis; FEV1 between 30% and 90%. mannitol 400mg dose or placebo. Follow-up 14 weeks 6 months/12 months 10 months Primary FEV1; FVC FEV1 FEV1 outcome Secondary outcomes Other measures of lung function; QoL; sputum microbiology; safety; sputum clearance and cough; respiratory symptoms. Other measures of lung function; FEV1 in patients on existing RhDNase treatment; pulmonary exacerbations; QoL; needs of antibiotics; safety; hospital and community care cost. Estimated cost and cost impact The cost of mannitol dry powder is currently unknown. n= 42; 8 to 18 years; cystic fibrosis; baseline FEV1 <70%; taking rhdnase for at least 4 weeks. mannitol 400mg for 12 weeks or dornase alpha 2.5mg for 12 weeks or combination. Airway inflammation; bacterial load in the lung; QoL; cost-effectiveness. Potential or intended impact speculative Patients Reduced morbidity Reduced mortality or increased survival Quicker, earlier or more accurate Other: diagnosis or identification of disease Improved quality of life for patients and/or carers None identified Services Increased use Service reorganisation required Staff or training required Decreased use of acute services if it improves lungs function. Other: None identified 4

5 Costs Increased unit cost compared to alternative New costs: Additive new therapy References Increased costs: more patients coming for treatment Savings: if respiratory function is maintained or exacerbations reduced. Increased costs: capital investment needed Other: 1 Suri R, Wallis C, Bush A et al. A comparative study of hypertonic saline, daily and alternate-day rhdnase in children with cystic fibrosis. Health Technology Assessment 2002;6(34). 2 National Screening Committee. National Screening Committee policy cystic fibrosis screening (in pregnancy). July National Screening Committee. National Screening Committee policy cystic fibrosis screening (neonatal). July Association of Chartered Physiotherapist in Cystic Fibrosis. Clinical guidelines for the physiotherapy management of cystic fibrosis. January The Cystic Fibrosis Trust s Clinical Standards and Accreditation Group. Standards for the clinical care of children and adults with cystic fibrosis in the UK Available at: (Accessed 15/01/2008). 6 Department of Health. Palliative care statistics for children and young adults. May Robinson M, Daviskas E, Eberl S et al. The effect of inhaled mannitol in bronchial mucus clearance on cystic fibrosis patients: a pilot study. European Respiratory Journal 1999;14: Clinicaltrials.gov. A phase 2 study to determine the safety and efficacy of inhaled dry powder mannitol in cystic fibrosis. NCT Available at: (Accessed 17/01/2008). 9 Clinicaltrials.gov. Mannitol dose response study in cystic fibrosis. NCT Available at: (Accessed 17/01/2008). 10 Clinicaltrials.gov. Long term administration of inhaled dry powder mannitol in cystic fibrosis - a safety and efficacy study. NCT Available at: (Accessed 17/01/2008). 11 Clinicaltrials.gov. Comparison of inhaled mannitol and rhdnase in children with cystic fibrosis. NCT Available at: (Accessed 18/01/2008). The National Institute for Health Research Research Programme is funded by the Department of Health. The views expressed in this publication are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health The, Department of Public Health and Epidemiology University of Birmingham, Edgbaston, Birmingham, B15 2TT, England Tel: +44 (0) Fax +44 (0)