Roflumilast (Daxas) for chronic obstructive pulmonary disease August 2009 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
Roflumilast (Daxas) for chronic obstructive pulmonary disease Target group Chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis in patients at risk of exacerbations maintenance therapy. Technology description Roflumilast (Daxas) is a long-acting selective phosphodiesterase-4 (PDE4) inhibitor which relieves the underlying symptoms of COPD through an anti-inflammatory effect. It acts by inhibition of synthesis of leukotriene B4 and reactive oxygen species in neutrophils, as well as inhibition of TNF-α release by mononuclear cells. Roflumilast also inhibits T-cell proliferation, cytokine production, and cell infiltration of the lungs. Roflumilast is administered orally at 500µg Innovation and/or advantages Roflumilast offers a novel mechanism of action as a first in class selective PDE4 inhibitor for COPD. In clinical trials of patients with COPD, it has been shown to improve lung function and reduce exacerbations. Developer Nycomed. Availability, launch or marketing dates, and licensing plans: Phase III clinical trials completed. NHS or Government priority area: This topic is relevant to The National Service Framework for Chronic Obstructive Pulmonary Disease (in development). Relevant guidance NICE clinical guideline. Chronic obstructive pulmonary disease - Management of chronic obstructive pulmonary disease in adults in primary and secondary care. 2004. Update expected June 2010 1. NICE interventional procedure guidance. Lung reduction volume surgery for advanced emphysema: guidance. 2005 2. NICE service guideline. Assisted-discharge service for patients with COPD. 2006 3. Clinical Knowledge Summaries. Chronic obstructive pulmonary disease. Care guideline. 2007 4. British Thoracic Society. Intermediate care - Hospital-at-Home in chronic obstructive pulmonary disease. 2007 5. British Thoracic Society. Current best practice for nebuliser treatment. 1997. Review expected January 2011 6. American Thoracic Society/European Respiratory Society. Statement on pulmonary rehabilitation. 2006 7. American Thoracic Society/European Respiratory Society. Standards for the diagnosis and management of patients with COPD. 2004. Review expected June 2010 8. 2
Clinical need and burden of disease COPD is a condition characterised by airflow obstruction a that is not fully reversible. The airflow obstruction is due to a combination of airway and parenchymal damage, and is usually progressive. COPD is associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily caused by cigarette smoking. Other factors, particularly occupational exposures, may also contribute to its development 1. Significant airflow obstruction may be present before the individual is aware of it. Common symptoms are breathlessness, cough, sputum, wheeze and chest tightness. COPD is a leading cause of morbidity and mortality in the UK. The number of patients on Quality and Outcomes Framework (QOF) disease registers with COPD was approximately 800,000 in the period 2007/08 with an unadjusted prevalence of 1.5% of all patients registered with a general practitioner in England 9. In 2006/07 there were 115,598 admissions to hospital with a primary diagnosis of COPD and 195,468 finished consultant episodes (ICD J40-J44; J47). Of the admissions, 105,266 (91%) were emergencies, which represented 0.8% of all emergency medical admissions to hospital. COPD accounted for 920,167 in-patient bed days, which represented almost 2% of all NHS in-patient bed days 10. There were 24,204 registered deaths from COPD in England and Wales in 2006, 90% of these being in the 65 and over age group 11. Existing comparators and treatments The NICE guideline 1 recommends the following treatment and support options for management of patients with stable COPD: Smoking cessation. Inhaled bronchodilator therapy: Short-acting beta 2 agonist, e.g. salbutamol. Short-acting antimuscarinic, e.g. ipratropium. Long-acting beta 2 agonist, e.g. salmeterol. Long-acting antimuscarinic, e.g. tiotropium. Theophylline - slow-release formulation. Corticosteroids: Inhaled corticosteroid, e.g. beclometasone dipropionate not licensed for use alone in COPD. Oral corticosteroid, e.g. prednisolone not recommended. Combination of the above. Efficacy and safety Trial Roflumilast 250µg, 500µg vs placebo; phase III. NCT00430729; roflumilast vs placebo, phase III. Roflumilast 500µg vs placebo. Sponsor Altana Pharma. Altana Pharma. Altana Pharma. Status Published 12. Published 13. Published 14. Location EU (inc UK), USA, Canada and other countries. EU (inc UK), Canada and Germany. other countries. Design Randomised, controlled, double-blind. Randomised, controlled, double-blind. Randomised, controlled, double-blind, crossover. Participants n=1,157; age >40 years; n=1,513; age 40 years; n=38; age 45-75 years; a Airflow obstruction is defined as a reduced FEV 1 (forced expiratory volume in 1 second) and a reduced FEV 1 /FVC ratio (where FVC is forced vital capacity), such that FEV 1 is less than 80% predicted and FEV 1 /FVC is less than 0.7 1. 3
and schedule smokers; postbronchodilator FEV 1 /FVC ratio 70% and FEV 1 30-80% predicted normal; FEV 1 reversibility of <12% and/or <200ml; stable concomitant and rescue short-acting bronchodilators allowed. Randomised to roflumilast 250µg, 500µg or placebo smokers; postbronchodilator FEV 1 /FVC ratio 70% and FEV 1 50% predicted normal; FEV 1 reversibility of 15% and/or 200ml. Inhaled corticosteroids or stable short-acting anticholinergics and rescue short-acting bronchodilators allowed. Randomised to roflumilast 500µg or placebo smokers; pre-bronchodilator post-bronchodilator FEV 1 35-75% predicted normal; FEV 1 reversibility of <12% or <200ml; sputum neutrophilia ( 45% nonsquamous cells), no exacerbation or upper respiratory tract infection (URTI) for 4 weeks; stable concomitant short-acting bronchodilators allowed. Randomised to roflumilast 500µg or placebo once daily for 4 weeks. Follow-up 24 weeks treatment period. 52 weeks treatment period. Two treatment periods of 4 weeks with a washout period of 4-6 weeks between. Primary Secondary Key results Adverse effects Trial Post-bronchodilator FEV 1 and St. George s Respiratory Questionnaire (SGRQ) total score. Pre and post-bronchodilator pulmonary function variables; COPD exacerbations. For roflumilast 250µg, 500µg and placebo respectively: post-bronchodilator FEV 1 improvement (SD): +74ml (+/-18) and + 97ml (+/- 18) p<0.001; mean exacerbations per patient 1.03, 0.75 and 1.13; change in total SGRQ score: -3.4, - 3.5 units and -1.8 units (both p-values <0.0001). Study withdrawal due to exacerbation or serious adverse events was similar between groups. Post-bronchodilator FEV 1, moderate to severe exacerbation rate. AURA (124), NCT00297102; roflumilast vs placebo; COPD and chronic bronchitis; phase III. SGRQ; pulmonary function; quality of life; safety. For roflumilast and placebo respectively: post-bronchodilator FEV 1 (SE): 39ml (+/-12ml) p=0.001; mean moderate or severe exacerbations per patient 0.86 and 0.92; change in total SGRQ score: -1.7 and -2.0 units p=0.651. Diarrhoea, nausea, headache. Percentage of sputum neutrophils. FEV 1, sputum neutrophils and other inflammatory cells, markers of activation of inflammatory cells and microvascular leakage in sputum. Significant reduction in neutrophils and eosinophils in sputum vs. placebo - 35.5% (p=0.002) vs 50% (p<0.001). Inflammatory markers significantly reduced by roflumilast compared with placebo. Post-bronchodilator FEV 1 improved significantly with roflumilast: mean difference vs placebo - 68.7ml (p=0.018). Diarrhoea, headache. HERMES (125) b, NCT00297115; roflumilast vs placebo; COPD and chronic bronchitis; phase III. Sponsor Nycomed. Nycomed. Status Completed, unpublished. Completed, unpublished. Location EU (inc UK), USA, Canada and other countries. EU (inc UK), USA, Canada and other countries. Design Randomised, controlled, double-blind. Randomised, controlled, double-blind. 4
Participants and schedule n=1,523; age 40 years; smokers; concomitant long-acting beta agonists (LABA) or short-acting anticholinergics allowed; at least 1 moderate and/or severe COPD exacerbation in last year; postbronchodilator FEV 1 50% of predicted normal value; total cough and sputum score 14. Randomised to roflumilast 500µg or placebo n=1,568; age 40 years; smokers; concomitant LABA or short-acting anticholinergics allowed; at least 1 moderate and/or severe documented COPD exacerbation in last year; postbronchodilator FEV 1 50% of predicted normal value; total cough and sputum score 14. Randomised to roflumilast 500µg or placebo Follow-up 52 weeks treatment period. 52 weeks treatment period. Primary Pre-bronchodilator FEV 1 ; COPD exacerbations. Pre-bronchodilator FEV 1 ; COPD exacerbations. Secondary Expected reporting date Trial Post-bronchodilator FEV 1 ; mortality time to death due to any reason; C-reactive protein (CRP); transition dyspnoea indices (TDI) focal score. Autumn 2009. Autumn 2009. EOS (127), NCT00313209; roflumilast vs placebo; COPD; phase III. Post-bronchodilator FEV 1 ; mortality time to death due to any reason; CRP; TDI focal score. HELIOS (128), NCT00424268; roflumilast vs placebo; COPD and chronic bronchitis; phase III. Sponsor Nycomed. Nycomed. Status Completed, unpublished 15. Completed, unpublished 15. Location EU (inc UK), Canada and South Africa. EU (inc UK), Canada and South Africa. Design Randomised, controlled, double-blind. Randomised, controlled, double-blind. Participants and schedule n=933; age >40 years; smokers; postbronchodilator FEV 1 between 40% and 70% of predicted normal; FEV 1 reversibility of 12% or 200ml; no recent COPD exacerbation. Randomised to roflumilast 500µg or placebo once daily; maintenance salmeterol 50µg twice daily. n=743; age >40 years; smokers; pre-treated with tiotropium for 3 months; postbronchodilator FEV 1 between 40% and 70% of predicted normal value; FEV 1 reversibility of 12% or 200ml recent COPD exacerbation. Randomised to roflumilast 500µg or placebo once daily; maintenance tiotropium 18µg Follow-up 24 weeks treatment period. 24 weeks treatment period. Primary Pre-bronchodilator FEV 1. Pre-bronchodilator FEV 1. s Secondary s Mild, moderate or severe COPD exacerbations; mean TDI focal score; shortness of breath questionnaire (SOBQ); spirometry parameters; CRP; cough and sputum. Post-bronchodilator FEV 1 ; moderate or severe COPD exacerbations; further spirometry parameters; CRP; cough and sputum. Key results Met primary endpoints. Met primary endpoints. Expected Autumn 2009. Autumn 2009. reporting date 5
Estimated cost and cost impact The cost of roflumilast is not yet known. The annual costs of licensed therapies for COPD are: Drug Dose Annual cost 16 Salmeterol (Serevent Accuhaler) 50µg twice daily 356 Tiotropium (Spiriva HandiHaler) 18µg once daily 451 Potential or intended impact speculative Patients Reduced morbidity Quicker, earlier or more accurate diagnosis or identification of disease Reduced mortality or increased length of survival Other: Improved quality of life for patients and/or carers: with once daily dosing None identified Services Increased use Service reorganisation required Staff or training required Decreased use: if length of stay and referrals reduced. Costs Increased unit cost compared to alternative New costs: References Other: Increased costs: more patients coming for treatment Savings: if exacerbations reduced. None identified Increased costs: capital investment needed Other: Unknown comparative cost 1 National Institute for Health and Clinical Excellence. Chronic obstructive pulmonary disease - Management of chronic obstructive pulmonary disease in adults in primary and secondary care. Clinical guideline CG12. London: NICE; February 2004. 2 National Institute for Health and Clinical Excellence. Lung reduction volume surgery for advanced emphysema: guidance. Interventional procedure guidance IPG114. London: NICE; February 2005. 3 National Institute for Health and Clinical Excellence. Assisted-discharge service for patients with COPD. London: NICE; October 2007. 4 Clinical Knowledge Summaries. Chronic obstructive pulmonary disease. Care guideline. August 2007. http://www.cks.library.nhs.uk/chronic_obstructive_pulmonary_disease Accessed 27 February 2009. 5 Stevenson R, Angus R, Blanchard M et al. Intermediate care - Hospital-at-Home in chronic obstructive pulmonary disease: British Thoracic Society guideline. Thorax 2007;62(3):200-210. 6 British Thoracic Society. Current best practice for nebuliser treatment. Care guideline. April 1997. 7 Nici L, Donner C, Wouters E et al. American Thoracic Society/European Respiratory Society statement on pulmonary rehabilitation. American Journal of Respiratory and Critical Care Medicine 2006;173(12):390 1413. 8 American Thoracic Society/European Respiratory Society. Standards for the diagnosis and management of patients with COPD. June 2004. 9 The Information Centre for Health and Social Care the Quality and Outcomes Framework. National level QOF tables 2007/08 prevalence. http://www.ic.nhs.uk/statistics-and-data-collections/supportinginformation/audits-and-performance/the-quality-and-s-framework/qof- 2007/08/data-tables Accessed 4 March 2008. 10 NHS. Hospital episode statistics. NHS England 2004-05. HES data 2006. www.hesonline.nhs.uk 11 Office for National Statistics. Mortality statistics: Deaths registered in 2006, DR_06, Newport: Office for National Statistics, 2008. 6
12 Rabe KF, Bateman ED, D O'Donnell et al. Roflumilast-an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005;366(9485):563-71. 13 Calverley PM, Sanchez-Toril F, McIvor A et al. Effect of 1-year treatment with roflumilast in severe chronic obstructive pulmonary disease. American Journal of Respiratory & Critical Care Medicine 2007;176(2):154-61. 14 Grootendorst DC, Gauw SA, Verhoosel RM et al. Reduction in sputum neutrophil and eosinophil numbers by the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007;62:1081-1087. 15 Press release. Nycomed s Daxas shows encouraging preliminary results. http://www.nycomed.com/en/menu/media/news+releases/pr_daxas_081028.htm Accessed 29 June 2009. 16 British Medical Association and Royal Pharmaceutical Society of Great Britain. British National Formulary. BMJ Group and RPS Publishing. London; March 2009. 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)121 414 7831 Fax +44 (0)121 414 2269 www.pcpoh.bham.ac.uk/publichealth/horizon 7