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Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study Ryo Okudan, Hidekazu Matsushima, Tomohiro Oba, Rie Kawabe, Minako Matsubayashi, Masako Amano, Tomotaka Nishizawa, Koujiro Honda Department of Respiratory Medicine, Saitama Red Cross Hospital, 8-3-33 Kami-ochiai, Chuo-ku, Saitama 338-8553, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few
Received 10 July 2015
treatment options. The efficacy of N-acetylcysteine in patients with IPF remains con-
Received in revised form
troversial. The aim of this research was to investigate the efficacy of inhaled
18 September 2015
N-acetylcysteine.
Accepted 12 October 2015
Methods: This study was designed as a single-center, single-arm, prospective clinical trial. Each patient who had IPF received 352.4 mg of inhaled N-acetylcysteine twice daily. Results: In total, 28 patients were enrolled. The mean values of the respiratory function
Keywords:
parameters at the initiation of therapy were as follows: forced vital capacity (FVC), 2.27 L
Forced vital capacity Idiopathic pulmonary fibrosis Inhalation Krebs von den Lungen-6 N-acetylcysteine
and %FVC, 76.2%. The mean change in FVC during 26 weeks prior to the inhaled N-acetylcysteine therapy was 170 mL, a significant decrease (p ¼0.019). The mean change in FVC during 26 weeks after the initiation of inhaled N-acetylcysteine therapy was 70 mL (p ¼0.06). When the patients were classified into two groups according to the degree of decline in FVC (Z 100 mL vs. o100 mL) during the 26-week period prior to the initiation of therapy, inhaled N-acetylcysteine showed a greater efficacy in attenuating FVC decline in the Z 100-mL group than in the o100-mL group. Conclusions: Inhaled N-acetylcysteine therapy was effective in patients with mild-tomoderate IPF and was more beneficial in patients who had greater declines in FVC before the initiation of therapy. (UMIN title: Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis, UMIN000016706, 2015/03/04.) & 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Abbreviations: IPF,
idiopathic pulmonary fibrosis; FVC,
forced vital capacity; VC, vital capacity; DLco,
diffusion capacity of the
lung for carbon monoxide; UIP, usual interstitial pneumonia; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D n Corresponding author. Tel.: þ81 48 852 1111; fax: þ81 48 852 1132. E-mail addresses: [email protected] (R. Okuda), [email protected] (H. Matsushima), [email protected] (T. Oba), [email protected] (R. Kawabe), [email protected] (M. Matsubayashi), skyfi[email protected] (M. Amano), [email protected] (T. Nishizawa), [email protected] (K. Honda). http://dx.doi.org/10.1016/j.resinv.2015.10.001 2212-5345/& 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
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1.
Introduction
Among the interstitial pneumonias, idiopathic pulmonary fibrosis (IPF) has an extremely poor prognosis, with approximately half of the patients with the disease dying within 2–3 years after diagnosis [1]. Reactive oxygen species are thought to be among the factors precipitating fibrosis in IPF. N-acetylcysteine can not only cause the direct elimination of these reactive oxyradicals, but it also can exert antifibrotic activity by inhibiting the production of inflammatory cytokines such as TNF-α and IL-1 [2,3]. In cases of severe IPF, the levels of glutathione in the lower respiratory tract are deficient, leading to an oxidation– reduction imbalance [4,5]. N-acetylcysteine also is generally recognized to have the capacity to improve this oxidation– reduction imbalance via metabolically converting itself to the antioxidant glutathione. The change in forced vital capacity (FVC) or vital capacity (VC) currently represents a highly reliable endpoint in the treatment of IPF [6]. The IFIGENIA trial, which was published in 2005, demonstrated significant differences between a three-drug regimen (oral N-acetylcysteine 600 mg three times daily, added to a standard regimen of prednisone and azathioprine) and a standard two-drug regimen (prednisoneþazathioprine), with regard to the deterioration of VC and diffusion capacity of the lung for carbon monoxide (DLco) [7]. On the other hand, in the PANTHER-IPF trial, which was published in 2014, no significant difference was observed in FVC change between the oral N-acetylcysteine group and the placebo group [8]. Thus, the efficacy of oral N-acetylcysteine therapy in patients with IPF remains controversial. In addition, a few reports have dealt with the efficacy of inhaled N-acetylcysteine therapy. Inhaled N-acetylcysteine therapy may be more effective than oral N-acetylcysteine therapy from the standpoint of ensuring that N-acetylcysteine reaches the lower respiratory tract. We conducted this study to clarify the trend of FVC change in patients with IPF who were treated with inhaled N-acetylcysteine therapy.
2.
Materials and methods
2.1.
Study design
This study was designed as a single-center, single-arm, prospective clinical trial and was conducted at the Saitama Red Cross Hospital in Japan. N-acetylcysteine was administered by inhalation at the dose of 352.4 mg twice daily (b.i.d.) via an ultrasonic nebulizer (NE-U22, Omron, Tokyo, Japan).
clinically known causes of UIP, such as drug-induced pneumonitis, collagen vascular diseases, and hypersensitivity pneumonitis. Concomitant therapy with only pirfenidone was permitted if the dose had been stable for 26 weeks before the experimental therapy. To assess the therapeutic responses in each subject, the study population comprised patients with IPF who had undergone pulmonary function tests at least 9 weeks prior to the initiation of the treatment. The criteria for withdrawal were as follows: discontinuation of treatment by the attending physician because the therapeutic effect was insufficient or because serious adverse events occurred and the patient withdrew consent. All patients provided written informed consent for participation in the N-acetylcysteine inhalation study. The present study was approved by the institutional review board of the Saitama Red Cross Hospital (IRB number, 20130109-2; date of registration, 2013/01/16).
2.3.
Efficacy and safety analysis
The primary endpoint was an absolute change in FVC at week 26 after the initiation of N-acetylcysteine therapy. We compared FVC change during the 26-week period prior to the initiation of therapy and the change during the 26 weeks after the initiation of therapy. Other assessment variables were the changes in the percentage of DLco (%DLco) and the absolute serum levels of interstitial pneumonia markers such as Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D). FVC, %DLco, and the serum levels of interstitial pneumonia markers were measured at 13-week intervals. Pulmonary function tests were measured with Chestac-33 (Chest, Tokyo, Japan). The frequency of acute exacerbations of IPF after the initiation of therapy also was checked. Acute exacerbation of IPF was diagnosed in accordance with the current Japanese guidelines; these included the fulfillment of all the following criteria: exclusion of overt infections and other disorders such as heart failure, pronounced dyspnea, findings of a honeycomb lung with newly appearing ground-glass opacities and infiltrates on high-resolution CT, and a decrease of Z 10 mmHg in the peripheral arterial oxygen tension [9]. Safety evaluation was performed by assessing the frequency of adverse events occurring from the initiation of Nacetylcysteine therapy to week 30 in terms of the system organ class and severity grade according to the Common Terminology Criteria for Adverse Events Version 4.0 [10]. Any untoward events that caused an aggravation in severity by 1 grade or more from the baseline were recorded as adverse events in this study.
2.2.
Subjects
The diagnosis of IPF and inclusion of subjects in the present study were based on the following criteria: patient age Z50 years, a usual interstitial pneumonia (UIP) pattern, or possible UIP pattern on high-resolution CT in accordance with the 2011 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association official statement on IPF [1], and the exclusion of other
2.4.
Estimation of sample size
The sample size of 15 patients was calculated to provide a paired t-test, a power of 80%, alpha error probability of 0.05 by the two-side test, and an effect size of 0.8. A minimum enrollment of 20 patients with an expected withdrawal rate of 30% was required.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
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Table 1 – Characteristics at the initiation of therapy.
Screened: 44
Characteristics
Excluded : 16 Did not have previous FVC data: 13 Concomitant therapy other than pirfenidone: 3
Received N-acetylcysteine: 28
Discontinued study: 5 Consent withdraw: 1 Chronic respiratory failure: 1 Adverse events: 2 Outpatient interruption: 1
Completed study: 23 (82%) Fig. 1 – Flow chart of patients. FVC, forced vital capacity.
2.5.
Statistical analysis
Data were analyzed using paired t-test, and p values o0.05 were considered statistically significant. The analysis was performed with the Excel Statistics software (SSRI Co., Ltd.).
3.
Results
3.1.
Patients enrolled
Between January 2013 and December 2014, 28 patients with a mean age of 72.1 years were enrolled in this study (Fig. 1). The lung function tests showed a restrictive pattern with diminished DLco (Table 1). The mean serum levels of both interstitial pneumonia markers were elevated: KL-6, 1301 U/mL (reference range: 0–500 U/mL) and SP-D, 249 ng/mL (reference range: 0– 110 ng/mL). The mean oxygen saturation by pulse oximetry was 96.871.0% at rest. The average of lowest oxygen saturation during the 6-min walk test was 89.474.9%. The mean decline in oxygen saturation by pulse oximetry during the 6min walk test was 7.4%. Of the 28 patients, 27 patients (96%) had not received any previous treatments, including steroids. There were 5 patients (18%) in whom the inhaled Nacetylcysteine therapy was discontinued (because of adverse events in 2 patients, progression of chronic respiratory failure in 1 patient, outpatient interruption in 1 patient, and withdrawal of consent in 1 patient).
3.2.
Efficacy
The mean change in FVC 26 weeks prior to the inhaled Nacetylcysteine therapy was 170 mL, a value representing a significant decrease (p ¼0.019). The mean change in FVC 26 weeks after the initiation of inhaled N-acetylcysteine therapy was 70 mL (p ¼0.06). Attenuation in the degree of decline in
Subjects Male Female
28 23 5
Age (yrs)
72.176.0
Smoking history Never smoker Current smoker Ex-smoker Pack-year
6 0 22 45.2727.6
Surgical lung biopsy (yes/no) Yes No
4 24
CT criteria for UIP in IPF ATS/ERS statement UIP pattern Possible UIP pattern
24 4
Physical findings Fine crackles (yes/no) Clubbed fingers (yes/no)
27/1 13/15
Prior treatment received No Yes (pirfenidone)
27 1
Blood tests KL-6 (U/mL) SP-D (ng/mL)
130171030 2497156
Pulmonary function FVC (L) FVC %pred (%) FEV1 (L) FEV1 %pred (%) FEV1/FVC (%) DLco %pred (%) DLco (mL/min/mmHg)
2.2770.76 76.2722.2 1.9170.57 91.0726.8 85.479.2 77.1731.5 11.774.8
6-min walk test Distance (m) SpO2 at rest (%) Lowest SpO2 (%)
4267124 96.871.0 89.474.9
Cardiac ultrasonography Right ventricular systolic pressure
26.1720.3
GAP stage (I/II/III)
18/7/3
Data are presented as n, n (%), or mean7standard deviation, unless otherwise stated. UIP, usual interstitial pneumonia; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; FVC, forced vital capacity; %pred, % predicted; FEV1, forced expiratory volume in 1 s; DLco, diffusion capacity of the lung for carbon monoxide; SpO2, oxygen saturation measured by pulse oximetry; GAP, gender age and physiology.
FVC was observed after 26 weeks of inhaled N-acetylcysteine therapy (Fig. 2). The %DLco tended to decrease by 6.7% in the 26 weeks prior to the treatment (p¼ 0.06), and %DLco still showed a 4.6% decline 26 weeks after the treatment (p ¼0.12).
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
4
-26 0
n = 28 Duration weeks from therapy initiation 0 13
26
-50 -100
-150 -200 -250 -300
p = 0.019
-26 200
Duration weeks from therapy initiation 0 13 n.s.
Table 2 – Absolute serum levels of interstitial pneumonia makers. Measurements
n
Initiation of therapy
Week 26
p Value
KL-6 (U/mL) SP-D (ng/mL)
28 28
130171030 2497156
10767612 2147118
0.047 0.13
The paired t-test was performed. Values are given as mean7 standard deviation. KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D.
The mean concentration of serum KL-6 was significantly lower at week 26 after the initiation of treatment than at the initiation of treatment (p¼ 0.047) (Table 2). Of the 28 patients, 1 patient developed an acute exacerbation of IPF, and 1 of the patients died of chronic respiratory failure during the treatment. None of the patients died of an acute exacerbation of IPF. When the patients were classified into two groups according to the degree of decline in FVC (Z 100 mL vs. o100 mL) during the 26-week period prior to the therapy initiation, FVC decline in the Z100-mL group during the 26-week period prior to the initiation of therapy was 370 mL (p¼ 0.015) and FVC decline in the Z100-mL group during the 26-week period after the initiation of therapy was 110 mL (p¼ 0.13). FVC decline in the o100-mL group during the 26-week period prior to the initiation of therapy was 5 mL (p ¼0.86) and FVC decline in the o100-mL group during the 26-week period after the initiation of therapy was 39 mL (p¼ 0.30). Inhaled N-acetylcysteine showed a greater efficacy in attenuating the decline in FVC in the Z100-mL group than in the o100-mL group (Fig. 3). There was little difference in the gender, age, and physiology (GAP) stage at the initiation of therapy between each group (the Z100-mL group: mean GAP stage 1.4 and theo100-mL group: mean GAP stage 1.5) [11].
Safety
Adverse events are listed in Table 3. Because of adverse events (drug-induced pneumonitis and cough), two patients were not
26
n.s.
0
-200
n.s.
-400 p = 0.015 -600 FVC decline
n.s.
Fig. 2 – Change in forced vital capacity (FVC). The paired t-test was used. Data are presented as mean7standard error. n.s., Not significant.
3.3.
Change from baseline in FVC (mL)
Change from baseline in FVC (mL)
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<100 mL (n = 15) ≥100 mL (n = 13)
Fig. 3 – Forced vital capacity (FVC) changes in two groups according to the degree of decline in FVC ( Z100 mL vs. o100 mL) during the 26-week period prior to the initiation of therapy. The paired t-test was used. Data are presented as mean7standard error. n.s., Not significant.
Table 3 – Summary of adverse events. Adverse events Cough Drug-induced pneumonitis Mediastinal emphysema
4 2 1 1
(14.3) (7.1) (3.6) (3.6)
Data are presented as n, n (%).
able to continue the study. The patient who was diagnosed with drug-induced pneumonitis by inhaled N-acetylcysteine was positive in a drug provocation test. Following discontinuation of inhaled N-acetylcysteine, the symptoms (fever and nasal discharge) and ground-glass opacities improved [12]. Cough leading to discontinuation of the study was improved simply by discontinuing N-acetylcysteine inhalation. Mediastinal emphysema was mild and the patient was able to continue inhaled N-acetylcysteine therapy. All adverse events were generally mild to moderate in severity and left no sequelae; inhaled N-acetylcysteine generally was well tolerated.
4.
Discussion
The present study demonstrated that inhaled N-acetylcysteine significantly attenuated the degree of decline in FVC in patients with mild to moderate IPF, particularly in those with progressive disease. Because of the low prevalence and heterogeneity of the disease, the use of mortality as a primary endpoint in clinical trials or studies in IPF cases can be very difficult. It has been reported that changes in FVC or VC during a 6–12-month period can serve as a potent predictor of death in the following year [6]. FVC and VC currently are recognized as highly reliable evaluation variables in the treatment of IPF. There have been sporadic clinical trials and studies of oral N-acetylcysteine in patients with IPF; however, there have been few published clinical trials and studies of inhaled
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
N-acetylcysteine. In a previous clinical study of inhaled N-acetylcysteine therapy, the inhaled N-acetylcysteine treatment group (n¼ 10) showed a significantly better improvement of SpO2 in the 6-min walk test as well as better improvement of the serum KL-6 level than the control group (n¼ 12), while no significant intergroup difference was noted for the change in %VC or %DLco [13]. Furthermore, another study conducted in patients with early-stage IPF suggested no significant difference in the FVC change between the inhaled N-acetylcysteine therapy group (n¼ 38) and the untreated group (n ¼38) [14]. Several reports have shown the efficacy of pirfenidone on the basis of the pretreatment and posttreatment measurements of FVC in the same series of patients with IPF [15–17]. The present study investigated the efficacy of inhaled N-acetylcysteine therapy in a similar fashion and was the first to prove the effect of attenuating the degree of FVC decline. Results with a combination therapy have been reported. Compared to pirfenidone alone, the combination of pirfenidone and inhaled NAC resulted in less FVC decline [15]. No significant difference in the attenuation of the degree of decline in FVC was observed between the oral N-acetylcysteine group and the placebo group in the PANTHER-IPF trial [8]. In addition, oral or intravenous administration of N-acetylcysteine resulted in an elevation of the plasma N-acetylcysteine concentrations; however, little or no Nacetyl`cysteine could be detected in the lung tissues or alveolar epithelial lining fluid [18–20]. A few studies confirmed that N-acetylcysteine or glutathione administered by inhalation increased the glutathione concentration and decreased the superoxide anion in the alveolar epithelial lining fluid [2,21]. Thus, it would appear that inhaled N-acetylcysteine therapy may be more effective than oral N-acetylcysteine therapy. The effect of the therapy was more pronounced in the group with a greater decline of FVC during the 26-week period prior to the initiation of therapy in this study. Therefore, it may be possible that the pretreatment rate of disease progression influences the efficacy of inhaled N-acetylcysteine. It seems important not only to take into account FVC at the initiation of treatment but also to pay heed to the pretreatment FVC changes. A similar finding has been reported with pirfenidone [16]. The disease may be associated with upregulated inflammation and fibrosis in patients with a greater decline in FVC during the 26-week period prior to the therapy. N-acetylcysteine compound with anti-inflammatory and antifibrotic effects may be more effective in patients with a greater decline in FVC. Some clinical trials have reported that FVC decreased by approximately 150–240 mL over a 12-month period in patients with mild to moderate IPF who were administered placebo [8,22]; on the other hand, in the present study, FVC decreased by as much as 170 mL over a 26-week period prior to N-acetylcysteine therapy. A decline in saturation of 4% or more during the 6-min walk test was a significant predictor of mortality [23]. The mean desaturation during the 6-min walk test was more than 4% in the present study; a large number of patients with a poor prognosis might have been included in the present study. An improvement tendency in the interstitial pneumonia markers was displayed following inhaled N-acetylcysteine therapy in the present study. According to sporadic reports,
5
serum KL-6 and SP-D may serve as predictors of disease activity in patients with IPF [24], and it would appear that inhaled N-acetylcysteine therapy may have been effective not only on FVC but also on interstitial pneumonia markers in the present study. According to previous reports, the concentration of serum KL-6 was decreased by inhaled NAC [13,25]. Some patients developed a cough in the present study. In one previous study of inhaled N-acetylcysteine, cough was the major adverse event [14]. However, in a previous study of oral N-acetylcysteine, cough was not the common adverse event [8]; this suggested that cough may be a consequence of the method of drug administration and not of the drug itself. The present study had several limitations. First, it was not a multicenter, double-blind, placebo-controlled trial; therefore, it is possible that the present study was not sufficient for reliable evaluation. Second, multivariate analysis could not be conducted because of the small sample size. Third, patient selection bias existed in the present study. The patients who had mild to moderate IPF were selected because the patients who were enrolled in this study needed to undergo pulmonary function tests, and the patients using concomitant therapy with medication other than pirfenidone were excluded. Fourth, the present test was conducted over a short period. It has been reported that the changes in FVC during a 6-month period can serve as potent predictors of poor outcomes [6]. In several reports, the efficacy of the pirfenidone treatment was confirmed by comparing the FVC change during the 26-week period prior to the initiation of therapy to the FVC change during the 26 weeks after the initiation of therapy [15–17]. The FVC decline during the 26-week period has been recognized as a reliable evaluation for the treatment of IPF.
5.
Conclusions
Our results indicated that inhaled N-acetylcysteine was effective in attenuating the degree of FVC decline and was well tolerated in patients with mild to moderate IPF. Inhaled Nacetylcysteine therapy was more beneficial in patients with a greater decline in FVC during the 26-week period before the initiation of the therapy. Further investigation of the efficacy of inhaled N-acetylcysteine therapy will be necessary.
Conflict of interest All authors have no conflicts of interest.
Acknowledgments The authors would like to thank Dr. T. Izumo (Department of Endoscopy, National Cancer Center Hospital) for his assistance in revising the manuscript and Enago (www.enago.jp) for the English language review. The authors received no financial support.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
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[13] Tomioka H, Kuwata Y, Inaka K, et al. A pilot study of aerosolized N-acetylcysteine for idiopathic pulmonary fibrosis. Respirology 2005;10:449–55. [14] Homma S, Azuma A, Taniguchi H, et al. Efficacy of inhaled Nacetylcysteine monotherapy in patients with early stage idiopathic pulmonary fibrosis. Respirology 2012;17:467–77. [15] Sakamoto S, Muramatsu Y, Satoh K, et al. Effectiveness of combined therapy with pirfenidone and inhaled Nacetylcysteine for advanced idiopathic pulmonary fibrosis: a case-control study. Respirology 2015;20:445–52. [16] Okuda R, Hagiwara R, Baba T, et al. Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice. Respir Med 2013;107:1431–7. [17] Sakamoto S, Itoh T, Muramatsu Y, et al. Efficacy of pirfenidone in patients with advanced-stage idiopathic pulmonary fibrosis. Intern Med 2013;52:2495–501. [18] Rodenstein D, DeCoster A, Gazzaniga A. Pharmacokinetics of oral acetylcysteine absorption, binding and metabolism in patients with respiratory disorders. Clin Pharmacokinet 1978;3:247–54. [19] Cotgreave I, Eklund A, Larsson A, et al. No penetration of orally administered N-acetylcysteine into bronchoalveolar lavage fluid. Eur J Respir Dis 1987;70:73–7. [20] Bridgeman MME, Marsden M, Selby C, et al. Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue. Thorax 1994;49:670–5. [21] Hagiwara S, Ishii Y, Kitamura S. Aerosolized administration of N-acetylcysteine attenuates lung fibrosis induced by bleomycin in mice. Am J Respir Crit Care Med 2000;162:225–31. [22] Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071–82. [23] Lama VN, Flaherty KR, Toews GB, et al. Prognostic value of desaturation during a 6-minute walk test in idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2003;168:1084–90. [24] Yokoyama A, Kohno N, Hamada H, et al. Circulating KL-6 predicts the outcome of rapidly progressive idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998;158:1680–4. [25] Bando M, Hosono T, Mato N, et al. Long-term efficacy of inhaled N-acetylcysteine in patients with idiopathic pulmonary fibrosis. Intern Med 2010;49:2289–96.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
Contents lists available at ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study Ryo Okudan, Hidekazu Matsushima, Tomohiro Oba, Rie Kawabe, Minako Matsubayashi, Masako Amano, Tomotaka Nishizawa, Koujiro Honda Department of Respiratory Medicine, Saitama Red Cross Hospital, 8-3-33 Kami-ochiai, Chuo-ku, Saitama 338-8553, Japan
art i cle i nfo
ab st rac t
Article history:
Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few
Received 10 July 2015
treatment options. The efficacy of N-acetylcysteine in patients with IPF remains con-
Received in revised form
troversial. The aim of this research was to investigate the efficacy of inhaled
18 September 2015
N-acetylcysteine.
Accepted 12 October 2015
Methods: This study was designed as a single-center, single-arm, prospective clinical trial. Each patient who had IPF received 352.4 mg of inhaled N-acetylcysteine twice daily. Results: In total, 28 patients were enrolled. The mean values of the respiratory function
Keywords:
parameters at the initiation of therapy were as follows: forced vital capacity (FVC), 2.27 L
Forced vital capacity Idiopathic pulmonary fibrosis Inhalation Krebs von den Lungen-6 N-acetylcysteine
and %FVC, 76.2%. The mean change in FVC during 26 weeks prior to the inhaled N-acetylcysteine therapy was 170 mL, a significant decrease (p ¼0.019). The mean change in FVC during 26 weeks after the initiation of inhaled N-acetylcysteine therapy was 70 mL (p ¼0.06). When the patients were classified into two groups according to the degree of decline in FVC (Z 100 mL vs. o100 mL) during the 26-week period prior to the initiation of therapy, inhaled N-acetylcysteine showed a greater efficacy in attenuating FVC decline in the Z 100-mL group than in the o100-mL group. Conclusions: Inhaled N-acetylcysteine therapy was effective in patients with mild-tomoderate IPF and was more beneficial in patients who had greater declines in FVC before the initiation of therapy. (UMIN title: Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis, UMIN000016706, 2015/03/04.) & 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Abbreviations: IPF,
idiopathic pulmonary fibrosis; FVC,
forced vital capacity; VC, vital capacity; DLco,
diffusion capacity of the
lung for carbon monoxide; UIP, usual interstitial pneumonia; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D n Corresponding author. Tel.: þ81 48 852 1111; fax: þ81 48 852 1132. E-mail addresses: [email protected] (R. Okuda), [email protected] (H. Matsushima), [email protected] (T. Oba), [email protected] (R. Kawabe), [email protected] (M. Matsubayashi), skyfi[email protected] (M. Amano), [email protected] (T. Nishizawa), [email protected] (K. Honda). http://dx.doi.org/10.1016/j.resinv.2015.10.001 2212-5345/& 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
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respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
1.
Introduction
Among the interstitial pneumonias, idiopathic pulmonary fibrosis (IPF) has an extremely poor prognosis, with approximately half of the patients with the disease dying within 2–3 years after diagnosis [1]. Reactive oxygen species are thought to be among the factors precipitating fibrosis in IPF. N-acetylcysteine can not only cause the direct elimination of these reactive oxyradicals, but it also can exert antifibrotic activity by inhibiting the production of inflammatory cytokines such as TNF-α and IL-1 [2,3]. In cases of severe IPF, the levels of glutathione in the lower respiratory tract are deficient, leading to an oxidation– reduction imbalance [4,5]. N-acetylcysteine also is generally recognized to have the capacity to improve this oxidation– reduction imbalance via metabolically converting itself to the antioxidant glutathione. The change in forced vital capacity (FVC) or vital capacity (VC) currently represents a highly reliable endpoint in the treatment of IPF [6]. The IFIGENIA trial, which was published in 2005, demonstrated significant differences between a three-drug regimen (oral N-acetylcysteine 600 mg three times daily, added to a standard regimen of prednisone and azathioprine) and a standard two-drug regimen (prednisoneþazathioprine), with regard to the deterioration of VC and diffusion capacity of the lung for carbon monoxide (DLco) [7]. On the other hand, in the PANTHER-IPF trial, which was published in 2014, no significant difference was observed in FVC change between the oral N-acetylcysteine group and the placebo group [8]. Thus, the efficacy of oral N-acetylcysteine therapy in patients with IPF remains controversial. In addition, a few reports have dealt with the efficacy of inhaled N-acetylcysteine therapy. Inhaled N-acetylcysteine therapy may be more effective than oral N-acetylcysteine therapy from the standpoint of ensuring that N-acetylcysteine reaches the lower respiratory tract. We conducted this study to clarify the trend of FVC change in patients with IPF who were treated with inhaled N-acetylcysteine therapy.
2.
Materials and methods
2.1.
Study design
This study was designed as a single-center, single-arm, prospective clinical trial and was conducted at the Saitama Red Cross Hospital in Japan. N-acetylcysteine was administered by inhalation at the dose of 352.4 mg twice daily (b.i.d.) via an ultrasonic nebulizer (NE-U22, Omron, Tokyo, Japan).
clinically known causes of UIP, such as drug-induced pneumonitis, collagen vascular diseases, and hypersensitivity pneumonitis. Concomitant therapy with only pirfenidone was permitted if the dose had been stable for 26 weeks before the experimental therapy. To assess the therapeutic responses in each subject, the study population comprised patients with IPF who had undergone pulmonary function tests at least 9 weeks prior to the initiation of the treatment. The criteria for withdrawal were as follows: discontinuation of treatment by the attending physician because the therapeutic effect was insufficient or because serious adverse events occurred and the patient withdrew consent. All patients provided written informed consent for participation in the N-acetylcysteine inhalation study. The present study was approved by the institutional review board of the Saitama Red Cross Hospital (IRB number, 20130109-2; date of registration, 2013/01/16).
2.3.
Efficacy and safety analysis
The primary endpoint was an absolute change in FVC at week 26 after the initiation of N-acetylcysteine therapy. We compared FVC change during the 26-week period prior to the initiation of therapy and the change during the 26 weeks after the initiation of therapy. Other assessment variables were the changes in the percentage of DLco (%DLco) and the absolute serum levels of interstitial pneumonia markers such as Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D). FVC, %DLco, and the serum levels of interstitial pneumonia markers were measured at 13-week intervals. Pulmonary function tests were measured with Chestac-33 (Chest, Tokyo, Japan). The frequency of acute exacerbations of IPF after the initiation of therapy also was checked. Acute exacerbation of IPF was diagnosed in accordance with the current Japanese guidelines; these included the fulfillment of all the following criteria: exclusion of overt infections and other disorders such as heart failure, pronounced dyspnea, findings of a honeycomb lung with newly appearing ground-glass opacities and infiltrates on high-resolution CT, and a decrease of Z 10 mmHg in the peripheral arterial oxygen tension [9]. Safety evaluation was performed by assessing the frequency of adverse events occurring from the initiation of Nacetylcysteine therapy to week 30 in terms of the system organ class and severity grade according to the Common Terminology Criteria for Adverse Events Version 4.0 [10]. Any untoward events that caused an aggravation in severity by 1 grade or more from the baseline were recorded as adverse events in this study.
2.2.
Subjects
The diagnosis of IPF and inclusion of subjects in the present study were based on the following criteria: patient age Z50 years, a usual interstitial pneumonia (UIP) pattern, or possible UIP pattern on high-resolution CT in accordance with the 2011 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association official statement on IPF [1], and the exclusion of other
2.4.
Estimation of sample size
The sample size of 15 patients was calculated to provide a paired t-test, a power of 80%, alpha error probability of 0.05 by the two-side test, and an effect size of 0.8. A minimum enrollment of 20 patients with an expected withdrawal rate of 30% was required.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
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respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
Table 1 – Characteristics at the initiation of therapy.
Screened: 44
Characteristics
Excluded : 16 Did not have previous FVC data: 13 Concomitant therapy other than pirfenidone: 3
Received N-acetylcysteine: 28
Discontinued study: 5 Consent withdraw: 1 Chronic respiratory failure: 1 Adverse events: 2 Outpatient interruption: 1
Completed study: 23 (82%) Fig. 1 – Flow chart of patients. FVC, forced vital capacity.
2.5.
Statistical analysis
Data were analyzed using paired t-test, and p values o0.05 were considered statistically significant. The analysis was performed with the Excel Statistics software (SSRI Co., Ltd.).
3.
Results
3.1.
Patients enrolled
Between January 2013 and December 2014, 28 patients with a mean age of 72.1 years were enrolled in this study (Fig. 1). The lung function tests showed a restrictive pattern with diminished DLco (Table 1). The mean serum levels of both interstitial pneumonia markers were elevated: KL-6, 1301 U/mL (reference range: 0–500 U/mL) and SP-D, 249 ng/mL (reference range: 0– 110 ng/mL). The mean oxygen saturation by pulse oximetry was 96.871.0% at rest. The average of lowest oxygen saturation during the 6-min walk test was 89.474.9%. The mean decline in oxygen saturation by pulse oximetry during the 6min walk test was 7.4%. Of the 28 patients, 27 patients (96%) had not received any previous treatments, including steroids. There were 5 patients (18%) in whom the inhaled Nacetylcysteine therapy was discontinued (because of adverse events in 2 patients, progression of chronic respiratory failure in 1 patient, outpatient interruption in 1 patient, and withdrawal of consent in 1 patient).
3.2.
Efficacy
The mean change in FVC 26 weeks prior to the inhaled Nacetylcysteine therapy was 170 mL, a value representing a significant decrease (p ¼0.019). The mean change in FVC 26 weeks after the initiation of inhaled N-acetylcysteine therapy was 70 mL (p ¼0.06). Attenuation in the degree of decline in
Subjects Male Female
28 23 5
Age (yrs)
72.176.0
Smoking history Never smoker Current smoker Ex-smoker Pack-year
6 0 22 45.2727.6
Surgical lung biopsy (yes/no) Yes No
4 24
CT criteria for UIP in IPF ATS/ERS statement UIP pattern Possible UIP pattern
24 4
Physical findings Fine crackles (yes/no) Clubbed fingers (yes/no)
27/1 13/15
Prior treatment received No Yes (pirfenidone)
27 1
Blood tests KL-6 (U/mL) SP-D (ng/mL)
130171030 2497156
Pulmonary function FVC (L) FVC %pred (%) FEV1 (L) FEV1 %pred (%) FEV1/FVC (%) DLco %pred (%) DLco (mL/min/mmHg)
2.2770.76 76.2722.2 1.9170.57 91.0726.8 85.479.2 77.1731.5 11.774.8
6-min walk test Distance (m) SpO2 at rest (%) Lowest SpO2 (%)
4267124 96.871.0 89.474.9
Cardiac ultrasonography Right ventricular systolic pressure
26.1720.3
GAP stage (I/II/III)
18/7/3
Data are presented as n, n (%), or mean7standard deviation, unless otherwise stated. UIP, usual interstitial pneumonia; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D; FVC, forced vital capacity; %pred, % predicted; FEV1, forced expiratory volume in 1 s; DLco, diffusion capacity of the lung for carbon monoxide; SpO2, oxygen saturation measured by pulse oximetry; GAP, gender age and physiology.
FVC was observed after 26 weeks of inhaled N-acetylcysteine therapy (Fig. 2). The %DLco tended to decrease by 6.7% in the 26 weeks prior to the treatment (p¼ 0.06), and %DLco still showed a 4.6% decline 26 weeks after the treatment (p ¼0.12).
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
4
-26 0
n = 28 Duration weeks from therapy initiation 0 13
26
-50 -100
-150 -200 -250 -300
p = 0.019
-26 200
Duration weeks from therapy initiation 0 13 n.s.
Table 2 – Absolute serum levels of interstitial pneumonia makers. Measurements
n
Initiation of therapy
Week 26
p Value
KL-6 (U/mL) SP-D (ng/mL)
28 28
130171030 2497156
10767612 2147118
0.047 0.13
The paired t-test was performed. Values are given as mean7 standard deviation. KL-6, Krebs von den Lungen-6; SP-D, surfactant protein-D.
The mean concentration of serum KL-6 was significantly lower at week 26 after the initiation of treatment than at the initiation of treatment (p¼ 0.047) (Table 2). Of the 28 patients, 1 patient developed an acute exacerbation of IPF, and 1 of the patients died of chronic respiratory failure during the treatment. None of the patients died of an acute exacerbation of IPF. When the patients were classified into two groups according to the degree of decline in FVC (Z 100 mL vs. o100 mL) during the 26-week period prior to the therapy initiation, FVC decline in the Z100-mL group during the 26-week period prior to the initiation of therapy was 370 mL (p¼ 0.015) and FVC decline in the Z100-mL group during the 26-week period after the initiation of therapy was 110 mL (p¼ 0.13). FVC decline in the o100-mL group during the 26-week period prior to the initiation of therapy was 5 mL (p ¼0.86) and FVC decline in the o100-mL group during the 26-week period after the initiation of therapy was 39 mL (p¼ 0.30). Inhaled N-acetylcysteine showed a greater efficacy in attenuating the decline in FVC in the Z100-mL group than in the o100-mL group (Fig. 3). There was little difference in the gender, age, and physiology (GAP) stage at the initiation of therapy between each group (the Z100-mL group: mean GAP stage 1.4 and theo100-mL group: mean GAP stage 1.5) [11].
Safety
Adverse events are listed in Table 3. Because of adverse events (drug-induced pneumonitis and cough), two patients were not
26
n.s.
0
-200
n.s.
-400 p = 0.015 -600 FVC decline
n.s.
Fig. 2 – Change in forced vital capacity (FVC). The paired t-test was used. Data are presented as mean7standard error. n.s., Not significant.
3.3.
Change from baseline in FVC (mL)
Change from baseline in FVC (mL)
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
<100 mL (n = 15) ≥100 mL (n = 13)
Fig. 3 – Forced vital capacity (FVC) changes in two groups according to the degree of decline in FVC ( Z100 mL vs. o100 mL) during the 26-week period prior to the initiation of therapy. The paired t-test was used. Data are presented as mean7standard error. n.s., Not significant.
Table 3 – Summary of adverse events. Adverse events Cough Drug-induced pneumonitis Mediastinal emphysema
4 2 1 1
(14.3) (7.1) (3.6) (3.6)
Data are presented as n, n (%).
able to continue the study. The patient who was diagnosed with drug-induced pneumonitis by inhaled N-acetylcysteine was positive in a drug provocation test. Following discontinuation of inhaled N-acetylcysteine, the symptoms (fever and nasal discharge) and ground-glass opacities improved [12]. Cough leading to discontinuation of the study was improved simply by discontinuing N-acetylcysteine inhalation. Mediastinal emphysema was mild and the patient was able to continue inhaled N-acetylcysteine therapy. All adverse events were generally mild to moderate in severity and left no sequelae; inhaled N-acetylcysteine generally was well tolerated.
4.
Discussion
The present study demonstrated that inhaled N-acetylcysteine significantly attenuated the degree of decline in FVC in patients with mild to moderate IPF, particularly in those with progressive disease. Because of the low prevalence and heterogeneity of the disease, the use of mortality as a primary endpoint in clinical trials or studies in IPF cases can be very difficult. It has been reported that changes in FVC or VC during a 6–12-month period can serve as a potent predictor of death in the following year [6]. FVC and VC currently are recognized as highly reliable evaluation variables in the treatment of IPF. There have been sporadic clinical trials and studies of oral N-acetylcysteine in patients with IPF; however, there have been few published clinical trials and studies of inhaled
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
respiratory investigation ] (] ] ] ]) ] ] ] –] ] ]
N-acetylcysteine. In a previous clinical study of inhaled N-acetylcysteine therapy, the inhaled N-acetylcysteine treatment group (n¼ 10) showed a significantly better improvement of SpO2 in the 6-min walk test as well as better improvement of the serum KL-6 level than the control group (n¼ 12), while no significant intergroup difference was noted for the change in %VC or %DLco [13]. Furthermore, another study conducted in patients with early-stage IPF suggested no significant difference in the FVC change between the inhaled N-acetylcysteine therapy group (n¼ 38) and the untreated group (n ¼38) [14]. Several reports have shown the efficacy of pirfenidone on the basis of the pretreatment and posttreatment measurements of FVC in the same series of patients with IPF [15–17]. The present study investigated the efficacy of inhaled N-acetylcysteine therapy in a similar fashion and was the first to prove the effect of attenuating the degree of FVC decline. Results with a combination therapy have been reported. Compared to pirfenidone alone, the combination of pirfenidone and inhaled NAC resulted in less FVC decline [15]. No significant difference in the attenuation of the degree of decline in FVC was observed between the oral N-acetylcysteine group and the placebo group in the PANTHER-IPF trial [8]. In addition, oral or intravenous administration of N-acetylcysteine resulted in an elevation of the plasma N-acetylcysteine concentrations; however, little or no Nacetyl`cysteine could be detected in the lung tissues or alveolar epithelial lining fluid [18–20]. A few studies confirmed that N-acetylcysteine or glutathione administered by inhalation increased the glutathione concentration and decreased the superoxide anion in the alveolar epithelial lining fluid [2,21]. Thus, it would appear that inhaled N-acetylcysteine therapy may be more effective than oral N-acetylcysteine therapy. The effect of the therapy was more pronounced in the group with a greater decline of FVC during the 26-week period prior to the initiation of therapy in this study. Therefore, it may be possible that the pretreatment rate of disease progression influences the efficacy of inhaled N-acetylcysteine. It seems important not only to take into account FVC at the initiation of treatment but also to pay heed to the pretreatment FVC changes. A similar finding has been reported with pirfenidone [16]. The disease may be associated with upregulated inflammation and fibrosis in patients with a greater decline in FVC during the 26-week period prior to the therapy. N-acetylcysteine compound with anti-inflammatory and antifibrotic effects may be more effective in patients with a greater decline in FVC. Some clinical trials have reported that FVC decreased by approximately 150–240 mL over a 12-month period in patients with mild to moderate IPF who were administered placebo [8,22]; on the other hand, in the present study, FVC decreased by as much as 170 mL over a 26-week period prior to N-acetylcysteine therapy. A decline in saturation of 4% or more during the 6-min walk test was a significant predictor of mortality [23]. The mean desaturation during the 6-min walk test was more than 4% in the present study; a large number of patients with a poor prognosis might have been included in the present study. An improvement tendency in the interstitial pneumonia markers was displayed following inhaled N-acetylcysteine therapy in the present study. According to sporadic reports,
5
serum KL-6 and SP-D may serve as predictors of disease activity in patients with IPF [24], and it would appear that inhaled N-acetylcysteine therapy may have been effective not only on FVC but also on interstitial pneumonia markers in the present study. According to previous reports, the concentration of serum KL-6 was decreased by inhaled NAC [13,25]. Some patients developed a cough in the present study. In one previous study of inhaled N-acetylcysteine, cough was the major adverse event [14]. However, in a previous study of oral N-acetylcysteine, cough was not the common adverse event [8]; this suggested that cough may be a consequence of the method of drug administration and not of the drug itself. The present study had several limitations. First, it was not a multicenter, double-blind, placebo-controlled trial; therefore, it is possible that the present study was not sufficient for reliable evaluation. Second, multivariate analysis could not be conducted because of the small sample size. Third, patient selection bias existed in the present study. The patients who had mild to moderate IPF were selected because the patients who were enrolled in this study needed to undergo pulmonary function tests, and the patients using concomitant therapy with medication other than pirfenidone were excluded. Fourth, the present test was conducted over a short period. It has been reported that the changes in FVC during a 6-month period can serve as potent predictors of poor outcomes [6]. In several reports, the efficacy of the pirfenidone treatment was confirmed by comparing the FVC change during the 26-week period prior to the initiation of therapy to the FVC change during the 26 weeks after the initiation of therapy [15–17]. The FVC decline during the 26-week period has been recognized as a reliable evaluation for the treatment of IPF.
5.
Conclusions
Our results indicated that inhaled N-acetylcysteine was effective in attenuating the degree of FVC decline and was well tolerated in patients with mild to moderate IPF. Inhaled Nacetylcysteine therapy was more beneficial in patients with a greater decline in FVC during the 26-week period before the initiation of the therapy. Further investigation of the efficacy of inhaled N-acetylcysteine therapy will be necessary.
Conflict of interest All authors have no conflicts of interest.
Acknowledgments The authors would like to thank Dr. T. Izumo (Department of Endoscopy, National Cancer Center Hospital) for his assistance in revising the manuscript and Enago (www.enago.jp) for the English language review. The authors received no financial support.
Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001
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Please cite this article as: Okuda R, et al. Efficacy and safety of inhaled N-acetylcysteine in idiopathic pulmonary fibrosis: A prospective, single-arm study. Respiratory Investigation (2015), http://dx.doi.org/10.1016/j.resinv.2015.10.001