Oral N-Acetylcysteine for Idiopathic Pulmonary Fibrosis

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2 Oral N-Acetylcysteine for Idiopathic Pulmonary Fibrosis 1.0 Summary for Patients N-acetylcysteine is taken by mouth to treat idiopathic pulmonary fibrosis (known as IPF), a longterm condition which stops the lungs working properly. N-acetylcysteine is taken to try to improve the way the lungs work. No medicine has been proved to help people with IPF live longer. More research is needed to show the best way to treat IPF. Patients need to reach an informed decision with their doctor as to the best treatment for them. IPF gets worse as time goes by. A study has shown that N-acetylcysteine might slow down the decline in lung function (breathing tests), but it did not appear to make patients feel less breathless. People taking N-acetylcysteine usually take it with prednisolone (a steroid) and a drug called azathioprine which affects the immune system. These medicines can have serious side effects. N-acetylcysteine itself did not cause important side effects in this study, and it may make azathioprine less harmful to the bone marrow when the two medicines are used together. 1.1 Summary for Healthcare Professionals The cause of idiopathic pulmonary fibrosis (IPF) is not known [1]. Possible causes are dysregulated wound healing and abnormal fibrotic reaction following repeated lung injury. The clinical course of IPF can be unpredictable with acute exacerbations. There is no strong evidence to favour one pharmacologic agent over another in the treatment of IPF since none are known to improve survival. But, for patients who wish to undergo a trial of treatment, options include N-acetylcysteine (NAC) monotherapy or in combination with prednisolone and azathioprine. In a randomised, double-blind trial, NAC was administered in combination with prednisone and azathioprine [2]. Compared to prednisone and azathioprine alone, the addition of NAC delayed the deterioration of laboratory measures of lung function, such as forced vital capacity (FVC). Unfortunately this was not translated into improved breathlessness or survival. When added to prednisone and azathioprine, NAC seems to have reduced the likelihood of druginduced myelotoxicity. NAC itself produced no significant side effects during the year of study. NAC effervescent tablets cost up to 920 per patient per year, excluding VAT [3]. No published health economics data were identified during this review. 2

3 The figure below highlights the balance of risks, benefits, evidence, costs and regulatory position for this intervention: Health benefits expected 3 2 Affordability 1 0 Safety Regulatory status Strength of evidence The data in the diagram above is taken from assessment against the standard options below: Health benefits expected Safety Strength of evidence Regulatory status Affordability Minor symptom control, or potential but unproven patient benefit Early death or substantial morbidity Speculative approach No UK licensed product. No licence globally Very significant costs above current best care option Symptom control, improved health related quality of life (HRQoL) Severe side effects affecting HRQoL Single case or small case series, uncontrolled studies No UK licensed product. Licensed products exist in USA/Europe but not necessarily for this intervention Increased costs above current best care option Major HRQoL gain e.g. months of life gained Moderate side effects Small controlled studies UK licensed product. Intervention offlabel in UK, and in USA/Europe Modest increased costs or cost neutral Transforming HRQoL e.g. years of life gained Minor side effects At least one large RCT UK licensed product. Intervention offlabel in UK but licensed in USA/Europe Cost saving compared with current best option 3

4 2.0 Intervention N-acetylcysteine (NAC) is available as tablets and effervescent tablets for the management of idiopathic pulmonary fibrosis (IPF). This is a rare condition, with a prevalence of 3 to 20 cases per 100,000 population [4]. It is a parenchymal lung disease [5] characterised by periods of relative stability which may be interspersed with episodes of progressively worsening symptoms of breathlessness and cough and declining lung function [6]. Pathology findings are of usual interstitial pneumonia [5]. The average survival is two to four years from diagnosis [7]. Aims of treatment are prevention of disease progression and optimisation of quality of life [8]. The cause of IPF is unknown, but is possibly the result of abnormal wound healing of repeated lung injuries [9]. NAC is a precursor of glutathione and acts as an antioxidant. It is thought to work in this condition by correcting or preventing glutathione depletion [10] and helping to reduce fibroproliferation [11]. The Map of Medicine notes that steroids are often used in IPF, but their efficacy has never been demonstrated and adverse effects are very common [9]. Steroids, azathioprine and cyclophosphamide are given as options in a joint American and European consensus statement [7], but there is little published evidence that they are effective [8] or alter the course of the disease. British Thoracic Society guidelines have given a 'weak' recommendation to use of NAC with azathioprine and prednisolone due to the limited evidence [6]. Lung transplantation can be considered for suitable patients [9]. Although iloprost and interferon gamma have been or are being studied in clinical trials for IPF, they are not currently licensed in the UK for this condition. In December 2010, the European Medicines Agency gave pirfenidone a positive opinion recommending the granting of a marketing authorisation [12] so it may reach the market shortly. In addition, macitentan [13] and ambrisentan [14] have been granted rare disease (orphan) status in Europe. However, the ARTEMIS-IPF trial of ambrisentan in IPF has been stopped [15] due to lack of efficacy [16]. NAC plus azathioprine and prednisone is currently being compared to NAC alone or placebo over 60 weeks in the PANTHER-IPF trial of patients with mild to moderate IPF [17]. 3.0 Review of Data Available Only one clinical trial has assessed the value and safety of NAC for treating IPF and this is summarised below: 3.1 Benefits A single randomised controlled trial of NAC has been conducted. IFIGENIA (Idiopathic Pulmonary Fibrosis International Group Exploring N-Acetylcysteine I Annual) was an industry-sponsored, double-blind trial [2]. Adults with a histological or radiologic pattern of usual interstitial pneumonia and disease for more than three months were included. Although 182 patients were randomised to treatment, 27 were not included in the efficacy analysis (due to diagnosis not being confirmed or withdrawal of consent). 72% of the participants were male, the mean age was 63 years and 5% were current smokers. Total lung capacity of participants was a mean of 62% of predicted value but twothirds of patients had a vital capacity of greater than 60%. 80 patients received oral NAC 600mg three times a day, as effervescent tablets, plus prednisone and azathioprine (standard therapy) for 12 months. A further 75 patients received matched placebo plus prednisone and azathioprine. All patients received usual care. The primary endpoints were changes in vital capacity (VC) and the diffusing capacity of the lungs for carbon monoxide (DL CO ) between baseline and month 12. Secondary outcomes included a dyspnoea score, CT scores of disease severity, mortality, and health status measured using the St. George s Respiratory Questionnaire. 4

5 Only 70% of the patients who took medication completed the study. For patients with baseline and last observation carried forward results, findings were quoted as least squares mean. At the end of the study, the VC for 71 NAC-treated patients was 2.27 L (standard error [SE] 0.05), compared to a baseline of 2.29 L (SE 0.68). The 68 patients given standard therapy alone achieved a VC of 2.10 L (SE 0.05) compared to a baseline VC of 2.36 L (SE 0.74). This gives an absolute difference of 0.18 L between interventions after 12 months in favour of NAC (95% CI 0.03 to 0.32), P=0.02. For DL CO the results were 3.85 mmol/min/kilopascal (SE 0.17) for NAC (n=68) and 3.10 mmol/min/kilopascal (SE 0.18) for standard therapy (n=63). These give a difference of 0.75 mmol/min/kilopascal (95% CI 0.27 to 1.23), P= No differences were seen in secondary outcomes including dyspnoea and health status. The trial was not powered to show a difference in mortality and one was not demonstrated (9% of patients on NAC died, and 11% on standard therapy, P<0.69). Summary This clinical trial compared oral NAC plus standard therapy (prednisone with azathioprine) with standard therapy alone [2]. Only 70% of patients who took medication completed the study. Whilst small, yet statistically significant, improvements were seen in some measures of lung function, there was no impact on dyspnoea or health status. 3.2 Strength of Evidence Few medicines for IPF have been tested in randomised, double-blind, controlled trials. One reason for this is that the number of patients is limited and a trial of adequate size would require multiple centres. Multicentre trials would require all those involved to agree uniform diagnostic criteria and outcome variables [18]. As symptoms and pathologies vary between patients, management must be individualised and the risks and benefits carefully weighed up [8]. The IFIGENIA trial was conducted to assess the ability of NAC plus prednisone and azathioprine to slow functional deterioration in patients with IPF [2]. The trial was properly randomised, with balanced groups and concealed allocation; both patients and clinicians were blinded to treatment allocation. However, the drop-out rate was about 70% in both groups of patients who took medication, which may have biased the results. The trial assessed surrogate outcomes of disease, VC and DLCO, and the difference between the two groups of patients was modest and probably of little clinical significance [19]. Particularly since the patient-focussed secondary outcomes showed no benefits on dyspnoea or mortality. It is possible that the benefit seen was not due to NAC alone, but due to the combination of NAC, steroid and immunosuppressant. This is now being further tested in the PANTHER-IPF trial [17]. No drug therapy has yet been shown to prolong survival in this condition [8]. NAC is inexpensive and easy to take but the trial did not demonstrate a large enough benefit to justify widespread use. The results from the selective group of patients studied cannot be easily extrapolated to those with more rapidly progressive disease seen in routine clinical practice [20]. 3.3 Risks In the IFIGENIA study, there was no difference in the number of patients reporting adverse events (90% with NAC and 89% with standard therapy). Most adverse events involved the respiratory tract 5

6 and were seen in similar numbers of patients in both groups. Only bone marrow toxicity showed a statistically significant difference: 4% with NAC and 13% on standard therapy (P=0.03) suggesting a possible protective effect of NAC to the myelotoxicity of azathioprine [2]. Only 70% of patients who took study medication completed the study so the results have to be interpreted with caution. Although there was little difference in adverse events between the two groups, long-term or rare adverse events are unknown. The delay in disease progression seen in the IFIGENIA study did not result in increased survival within the year of the study. Both arms of the trial were treated with azathioprine and prednisolone, which are not without their risks. 3.4 Regulatory Status Oral NAC is not available as a licensed medication in the UK but is available in countries such as Spain and Germany [3]. Tablets can be imported into the UK as a named patient medication. Even in countries where it is licensed, it does not have a marketing authorisation to treat IPF specifically, but for general respiratory tract disorders (as a mucolytic). 3.5 Affordability NAC effervescent tablets cost up to 920 per year per patient, excluding VAT [3]. As they are administered orally there are no associated costs. No relevant published health economics data were identified during this review. 6

7 4.0 References 1. Ryu JH and Daniels CE. Advances in the management of idiopathic pulmonary fibrosis. F1000 Medicine Reports 2010;2: Demedts M, Behr J, Buhl R et al for the IFIGENIA Study Group. High-Dose Acetylcysteine in Idiopathic Pulmonary Fibrosis. New Eng J Med 2005;353: Personal Communication. UL Medicines Ltd. 8/2/11 4. Selman M, Thannickal VJ, Pardo A et al. Idiopathic pulmonary fibrosis. Drugs 2004;64: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165: Wells AU, Hirani N et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008;63:V1-V58 7. American Thoracic Society and European Respiratory Society. Idiopathic pulmonary fibrosis: diagnosis and treatment. International Consensus Statement. Am J Respir Crit Care Med 2000;161: Meyer KC. Are there any promising therapies on the horizon? Idiopathic pulmonary fibrosis, part 2: the current approach to treatment. J Resp Dis 2007;28: Institute for Innovation and Improvement. Map of Medicine. Idiopathic pulmonary fibrosis (IPF). Accessed from on 28/1/ Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician 2009;80: Walter N, Collard HR, King Jr TE. Current perspectives on the treatment of idiopathic pulmonary fibrosis. Pro Am Thorac Soc 2006;3: European Medicines Agency. Esbriet positive opinion. Accessed from s/positive/human_smop_ jsp&murl=menus/medicines/medicines.jsp&mid=wc0b01ac d127&source=homeMedSearch&category=human on 9/2/ European Medicines Agency. Macitentan orphan drug status. Accessed from pdf on 9/2/ European Medicines Agency. Ambrisentan orphan drug status. Accessed from pdf on 9/2/ US National Institutes of Health. (ARTEMIS-IPF) Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF. Accessed from on 9/2/ Biospace. Gilead Sciences, Inc. (GILD) Terminates Phase III Clinical Trial of Ambrisentan in Patients with Idiopathic Pulmonary Fibrosis. Accessed from on 9/2/ US National Institutes of Health. Evaluating the Effectiveness of Prednisone, Azathioprine, and N- acetylcysteine in People With Idiopathic Pulmonary Fibrosis (PANTHER-IPF). Accessed from on 2/2/ Mason RJ, Schwarz MI, Hunninghake GW et al. Pharmacological therapy for idiopathic pulmonary fibrosis past, present, and future. Am J Respir Crit Care Med 1999;160: Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. New Engl J Med 2005;353: Wells AU. Antioxidant therapy in idiopathic pulmonary fibrosis: hope is kindled. Eur Resp J 2006;27:

8 5.0 Quality Assurance 5.1 Author Sue Gough, Wessex Drug and Medicines Information Centre, Southampton University Hospitals NHS Trust. 5.2 Checkers Dr Simon Wills, Wessex Drug and Medicines Information Centre, Southampton University Hospitals NHS Trust. 5.3 Expert Comment Dr K O Reilly, Lead Physician for Interstitial Lung Disease, Southampton University Hospitals NHS Trust. 8

9 6.0 Appendix 6.1 Search strategy The following strategy was used to find the evidence contained in this report: Medline (1950 to January 2011): acetylcysteine (exp) and pulmonary fibrosis (exp); limit to Humans and English language. Embase (1980 to January 2011): Embase: acetylcysteine.exp and lung fibrosis (exp); limit to humans and English language. Citations review for all papers retrieved via Embase and Medline. CRD Databases: acetylcysteine. No UK-based manufacturer/promoter, so not sent to pharmaceutical industry for comment. 6.2 Data selection Reasons for excluding papers Studies identified through Medline n=2 Studies identified through Embase n=2 Studies identified through other sources n=0 Studies identified through more than one source removed from count n=2 Studies screened n=2 Studies excluded n=1 because: exploratory analysis of previous study data (n=1) Studies included n=1 9

10 6.3 Acknowledgements None. 6.4 Declarations of Interest None declared from all those participating in the creation of this review. 6.5 Disclaimer This review relates solely to the medicine and clinical intervention described within the text and reflects UK practice. Should you have any doubts about whether it is relevant to a specific patient, or are unsure whether you understand it, seek appropriate professional assistance. The contents were believed to be an accurate reflection of the medical literature at the time of preparation. However, you should always consult the literature and take account of new developments. The authors are not responsible for the content of external websites and any links are made available solely to indicate their potential usefulness. You must use your judgement to determine the accuracy and relevance of the information they contain. 10