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Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial

Lancet Respir Med. 2016. doi:10.1016/S2213-2600(16)30044-3

Summary

Background

Oral acetylcysteine (also known as N-acetylcysteine) is used with pirfenidone to treat idiopathic pulmonary fibrosis (IPF) in Europe. However, no randomised studies have investigated the safety and tolerability of this combination. The PANORAMA study assessed the safety and tolerability of acetylcysteine combined with pirfenidone in patients with IPF. Exploratory efficacy endpoints were also assessed.

Methods

We did a double-blind randomised trial at 48 sites in eight countries. Patients with IPF aged 40–80 years and established on pirfenidone (at least 1602 mg/day for 8 weeks or longer) were randomly assigned in a 1:1 ratio by interactive voice response system to receive concomitant oral acetylcysteine (600 mg, three times daily) or placebo for 24 weeks. A stratified blocked randomisation scheme was used with a block size of 4. Randomisation was stratified by dose of pirfenidone (2403 mg/day [the maximum dose] or <2403 mg/day). Patients, physicians, study staff and the sponsor were masked to treatment group allocation. The primary endpoint was assessment of adverse events, which were collected at each visit and for 28 days after the last dose of study drug. Exploratory efficacy measurements included forced vital capacity (FVC), carbon monoxide diffusing capacity, and 6 min walk distance. Analyses were done in the modified intention-to-treat population, which included all patients who were randomised and received at least one dose of study medication. This study is registered with the European Clinical Trials Database (EudraCT number 2012-000564-14) and has been completed.

Findings

123 patients participated in the study between June 28, 2013, and Feb 24, 2015. 61 were assigned to the acetylcysteine group (60 received study medication and included in analysis) and 62 were assigned to the placebo group (all included in analysis). The occurrence of at least one adverse event (46 [77%] patients receiving acetylcysteine vs 50 [81%] receiving placebo), adverse events related to study treatment (17 [28%] vs 16 [26%]), and the number of patients experiencing severe adverse events (three [5%] vs two [3%]), life-threatening adverse events (one [2%] vs one [2%]), or death (one [2%] vs three [5%]) was similar between treatment groups. One case of diarrhoea in the acetylcysteine group was considered severe and related to study treatment. Nine serious adverse events were reported by seven patients: dyspnoea, headache, hypertension, intervertebral disc protrusion, and malignant lung neoplasm in the acetylcysteine group, and aortic aneurysm, contusion, forearm fracture, and worsening IPF in the placebo group. The most common adverse events were cough, nasopharyngitis, and diarrhoea. Photosensitivity occurred more frequently with acetylcysteine (eight [13%] patients) than placebo (one [2%] patient; difference 11·7%; 95% CI 2·6–20·9; p=0·016]), and was not attributable to differences in location, season, or concomitant medication. Four (7%) patients receiving acetylcysteine and three (5%) receiving placebo discontinued study treatment due to adverse events. In the exploratory analysis, change in FVC indicated that clinical benefit from addition of acetylcysteine to pirfenidone is unlikely, with the possibility of a harmful effect in patients with IPF (adjusted rate of decline 125·6 mL/6 months for acetylcysteine vs 34·3 mL/6 months for placebo; difference −91·3 mL; 95% CI −174·4 to −8·3; p=0·031).

Interpretation

Findings from the PANORAMA study suggest that addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile of pirfenidone, and is unlikely to be beneficial in IPF.

Funding

InterMune International AG (Roche).

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible lung disease that presents with exertional dyspnoea and cough.1 Patients with IPF have a poor prognosis, with 5 year survival of 20–40%2 and median survival from diagnosis of 2–5 years.3, 4, and 5 The prevalence of IPF in Europe and North America is believed to range from three to nine cases per 100 000,6 peaking in male current or former smokers in the seventh or eighth decade of life.3, 4, and 5

The only licensed treatments for IPF at present are pirfenidone and nintedanib; pirfenidone was approved in Europe in 20117 and in the USA in 2014,8 whereas nintedanib was approved at the same time as pirfenidone in the USA and in 2015 in Europe.9 and 10 Results from the phase 3 ASCEND11 and CAPACITY12 trials demonstrated that pirfenidone significantly reduced disease progression and improved survival.

Research in context

Evidence before this study

We searched PubMed for reports published in any language before Feb 25, 2016, using the terms “pirfenidone”, “N-acetylcysteine”, and “idiopathic pulmonary fibrosis”. This search generated 31 results. We excluded preclinical studies, review articles, and reports investigating topics other than treatment, leaving three clinical trials investigating the combination of pirfenidone and acetylcysteine in the treatment of idiopathic pulmonary fibrosis (IPF). The first was a small case-control study of inhaled acetylcysteine combined with pirfenidone in Japanese patients over 1 year, in which patients treated with combination therapy had a lower mean decline in forced vital capacity (FVC) versus patients receiving placebo and pirfenidone. However, interpretation of this study is limited by its small sample size and the use of inhaled rather than oral acetylcysteine. An observational study in Germany reported a higher frequency of adverse events in patients receiving combination therapy with oral acetylcysteine and pirfenidone versus pirfenidone alone. However, patients who received combination therapy had more advanced IPF at baseline, and a significant proportion were also receiving oral corticosteroids, which may have confounded results. The final study compared acetylcysteine and pirfenidone with acetylcysteine and placebo but did not include a pirfenidone and placebo group; therefore, conclusions could not be made regarding the safety or efficacy of adding oral acetylcysteine to pirfenidone.

Added value of this study

To our knowledge, our study is the first randomised controlled trial to investigate the safety and tolerability of oral acetylcysteine and pirfenidone compared with pirfenidone alone in patients with IPF. We found that the addition of acetylcysteine to pirfenidone does not significantly alter the safety and tolerability profile of pirfenidone, although we noted an increased incidence in photosensitivity with acetylcysteine which could not be explained by further analysis. Exploratory efficacy analyses suggested that patients receiving combination therapy experienced a greater decline in lung function versus patients treated with pirfenidone alone.

Implications of all the available evidence

Although acetylcysteine did not appear to significantly affect tolerability when combined with pirfenidone, our results suggest that the addition of oral acetylcysteine does not have a beneficial effect on lung function compared with pirfenidone alone. This observation is consistent with results from the PANTHER study where acetylcysteine monotherapy offered no significant benefit versus placebo with respect to the preservation of FVC in patients with IPF. Indeed, our results suggest a possible deleterious effect from combination therapy and argue against the use of acetylcysteine in combination with pirfenidone in the treatment of patients with IPF.

Several other unlicensed medications are used in the treatment of IPF, including acetylcysteine (also known as N-acetylcysteine), a precursor of the antioxidant glutathione.4 Clinical trial data on acetylcysteine for IPF include results from the IFIGENIA study,13 and 14 which suggested that the addition of acetylcysteine to prednisone and azathioprine slowed deterioration in lung function versus placebo. However, the triple combination was discontinued in the more recent PANTHER15 study due to an increased risk of harm versus placebo. The acetylcysteine monotherapy group of the PANTHER trial continued,16 but no benefit on forced vital capacity (FVC) was observed versus placebo. However, acetylcysteine might be efficacious in some subgroups of patients with IPF as indicated by a post-hoc analysis17 of data from the PANTHER study, which suggested that polymorphisms in the gene encoding toll-interacting protein (TOLLIP; rs3750920) might modify the response to acetylcysteine. The updated 2015 American Thoracic Society/European Respiratory Society clinical practice guidelines on the treatment of IPF18 acknowledged that further research is needed to determine whether some subgroups of patients might benefit from acetylcysteine therapy. However, the lack of evidence in support of either oral or inhaled acetylcysteine as an efficacious treatment for IPF led to a conditional recommendation against the use of acetylcysteine for the treatment of IPF.18 No recommendation was made regarding the combination of acetylcysteine with antifibrotic therapies.

In some European countries, up to a third of patients with IPF are reported to have received pirfenidone and acetylcysteine.19 and 20 Although the use of acetylcysteine is probably declining after publication of results from the PANTHER study,16 few clinical trials have investigated the combination of acetylcysteine and pirfenidone. In a small Japanese case-control study of 27 patients with recent disease progression, the use of acetylcysteine and pirfenidone was associated with improved outcomes compared with pirfenidone monotherapy. Adverse events were reported only in the combination group;21 however, it should be noted that this study used an inhaled formulation of acetylcysteine, delivered at a lower dose than is typically used for systemic delivery of acetylcysteine in Europe (inhaled acetylcysteine 352 mg twice daily vs oral acetylcysteine 600 mg three times daily).16 and 18 In a German real-world observational cohort of 63 patients receiving pirfenidone, adverse events and treatment discontinuations were more frequent in patients receiving combination therapy with pirfenidone and either oral acetylcysteine or corticosteroids, or both, than in patients receiving pirfenidone monotherapy.20

The PANORAMA study aimed to investigate the safety and tolerability of oral acetylcysteine 600 mg three times daily in combination with pirfenidone, compared with pirfenidone alone, in the treatment of IPF over 24 weeks. Prespecified exploratory efficacy endpoints were also investigated to provide preliminary evidence on the efficacy or harm of oral acetylcysteine when added to pirfenidone.

Methods

Study design and participants

The PANORAMA study was a phase 2, randomised, double-blind, placebo-controlled study. Eligible patients were aged 40–80 years with a diagnosis of IPF, recruited from hospitals at 48 study sites in eight countries (Austria, Belgium, Denmark, France, Germany, Italy, Sweden, and the UK). High-resolution computed tomography scans (one from diagnosis and one dated within a year of study inclusion) were assessed by a central reading committee to confirm that fibrotic changes were greater than the extent of emphysema. Patients were included if they had an FVC of 50–90%, carbon monoxide diffusing capacity of the lungs (DLCO) of 30–90% (DLCO 35–90% in Italy), and had been receiving pirfenidone 1602 mg/day or higher for at least 8 weeks before randomisation. Patients with severe or unstable concomitant disease were excluded from the study, as were those who would not agree to abstain from tobacco for the duration of the trial. During the study, patients were not permitted to receive any treatment for IPF other than the study medication (acetylcysteine or placebo) and pirfenidone, with the exception of corticosteroid courses lasting up to 21 days for acute IPF exacerbations. Country-specific variations in inclusion and exclusion criteria are presented in the appendix.

The study was done in accordance with the International Conference on Harmonisation Guidelines, the Declaration of Helsinki, and relevant local legal and regulatory requirements applicable to the countries in which the trial was conducted. Approval from institutional review boards or institutional ethics committees at each study site was obtained before the start of the study. Written informed consent was obtained from patients before screening. A data monitoring committee of independent experts was responsible for reviewing emerging adverse events throughout the trial.

Randomisation and masking

Patients received either acetylcysteine or placebo (both provided by Zambon SpA, Bresso, Italy). Acetylcysteine was administered as 600 mg dispersible tablets, taken orally three times daily in the absence of food. Placebo dispersible tablets, also administered orally three times daily in the absence of food, were indistinguishable from acetylcysteine tablets to maintain blinding. Pirfenidone (Roche, Basel, Switzerland) was continued throughout the 24 week study period and was administered orally three times daily with food. Patients were expected to receive 1602–2403 mg pirfenidone per day.

Patients were enrolled by the principal investigator at each site and randomised in a 1:1 ratio to receive acetylcysteine or placebo by an interactive voice response system. A stratified blocked randomisation scheme was used with a block size of 4. Randomisation was stratified by dose of pirfenidone (2403 mg/day [the maximum dose] or <2403 mg/day), to allow tolerability and efficacy comparisons of lower doses with the full dose. All randomisation codes were computer generated by a statistician independent to the conduct of the study.

Patients, physicians, study staff, and the sponsor were masked to treatment group allocation. To maintain blinding, study staff involved in conducting pulmonary function tests were not allowed to assess patients for adverse events or pulmonary symptoms. Treatment assignments were only unblinded once the study was complete, the database was locked, and the final analysis was complete.

Patients were asked to return all used and unused blister packages of study drug (acetylcysteine or placebo) for a review of treatment adherence at weeks 4, 12, and 24.

Outcomes

The primary objective of the study was to assess the safety and tolerability of acetylcysteine used in combination with pirfenidone in patients with IPF. Adverse events were collected at baseline and at each study visit (at weeks 4, 12, and 24). Follow-up lasted for 28 days after the final dose of study drug. IPF exacerbations were considered disease-related events that did not fall under the definition of an adverse event associated with the administration of study medication and therefore were not formally recorded. Prespecified exploratory efficacy measurements were also collected at baseline, week 12, and week 24, and included FVC, DLCO, 6 min walk distance (6MWD), the Borg Scale of Perceived Exertion, and the University of California San Diego Shortness of Breath Questionnaire (UCSD-SOBQ). Oxygen saturation was measured before and after the 6 min walk test.

Statistical analyses

No formal statistical power calculation was used to estimate the sample size. We originally planned to enrol 250 patients, based on the known frequency of adverse events and experience from previous trials. The number of patients to be enrolled in the PANORAMA study was reduced from 250 to 120 in a protocol amendment (finalised on June 18, 2014, when 100 patients had been enrolled) after publication of the PANTHER study results, which suggested that acetylcysteine did not have a beneficial role in treating IPF.16 A review of PANORAMA safety data at this point did not suggest any risk of harm and a decision was made to continue the trial but with a smaller sample size. The sample size of 120 patients (60 per group) was estimated to provide 30 patient-years per treatment group. With this sample size, a difference in incidence of treatment-emergent adverse events 15% or more between treatment groups could be demonstrated with 90% confidence (that is, the 90% CI excludes zero; post-hoc power calculation). In this small, phase 2 study, a difference of 15% in adverse events was considered to be a potential difference in the safety and tolerability of acetylcysteine and pirfenidone, compared with pirfenidone alone.

Analyses were done on the modified intention-to-treat population, which included all patients who were randomly assigned and received at least one dose of study medication (acetylcysteine or placebo). Safety and tolerability endpoints were summarised descriptively. We mapped adverse events according to system organ class and preferred terms in the Medical Dictionary for Regulatory Activities (version 11.0). p values from Fisher's exact test and the 95% CIs based on normal approximation are provided for numerically high differences in incidence between treatment groups for descriptive purposes. There was no prespecified minimum difference between groups for this calculation, although the minimum adverse event rate per group with a prespecified precision calculation was 5%.

Exploratory efficacy data, including FVC, DLCO, 6MWD, Borg Scale of Perceived Exertion, and UCSD-SOBQ, were also summarised descriptively. Absolute differences in change from baseline values for the exploratory efficacy endpoints were summarised with 95% CIs and post-hoc descriptive p values from the rank analysis of covariance, with the average standardised rank change as the outcome variable and the standardised rank baseline value as a covariate. Missing data due to death were assigned the worst ranks, with early deaths ranked worse than later deaths. Missing data due to other reasons were not imputed. Categorical analyses of FVC and 6MWD were done based on observed cases or deaths. A post-hoc slope analysis adjusted for age, sex, and height, with patient included as a random effect, was done to investigate the change in FVC volume over time in all patients, stratified by treatment group and also by baseline disease severity. No imputation was made for missing values.

All analyses were performed using the Statistical Analysis Software (SAS), version 9.2.

This study is registered with the European Clinical Trials Database (EudraCT number 2012-000564-14).

Role of the funding source

The sponsor, InterMune, and its designees, designed and conducted the study in collaboration with the academic investigators. The sponsor, and its designees, monitored the study, collected data, performed the statistical analysis, and wrote the clinical study report. Following the acquisition of InterMune by F Hoffmann-La Roche in 2014, Roche assumed these responsibilities. Manuscript drafts were prepared by the corresponding author with support from a medical writer funded by Roche. The authors had full access to all data in the study and the corresponding author had final responsibility for the decision to submit for publication. All authors met International Council of Medical Journal Editors criteria for authorship and did not receive payment for their involvement in manuscript preparation.

Results

123 patients were enrolled. The first patient entered the study on June 28, 2013, and the last patient completed the 28 day follow-up after 24 weeks of treatment on Feb 24, 2015. 61 patients were randomly assigned to the acetylcysteine group and 62 were randomly assigned to the placebo group. One patient in the acetylcysteine group did not receive the study drug and was excluded from the data analysis.

Baseline characteristics were generally well balanced between treatment groups, including lung function, with similar mean percent predicted FVC values in the acetylcysteine and placebo groups (table 1). Although inclusion criteria were different in Italy versus other countries for the lower limit of DLCO (35–90% vs 30–90%, respectively), the baseline DLCO in Italy was similar to that in Germany (the country with the largest number of enrolled patients). A high proportion of patients in both treatment groups reported comorbid conditions at baseline (appendix). There was some imbalance between treatment groups at baseline: in particular, more patients in the acetylcysteine group had cardiac disorders at baseline (32% [19/60] vs 18% [11/62]), whereas more patients in the placebo group had gastrointestinal disorders (53% [33/62] vs 37% [22/60]) or sleep apnoea syndrome (16% [10/62] vs 7% [4/60]). One patient in the acetylcysteine group was reported to have a medical history of emphysema. Concomitant medications were common in both treatment groups (appendix). More patients in the placebo group were receiving supplemental oxygen compared with the acetylcysteine group (13% [8/62] vs 3% [2/60]). Two (3%) patients in the placebo group received corticosteroids for acute exacerbation of IPF during the trial.

Table 1 Summary of baseline demographic characteristics

Pirfenidone plus acetylcysteine (n=60) Pirfenidone plus placebo (n=62)
Mean age, years 66·7 (8·0) 67·5 (6·2)
Age ≥65 years 37 (62%) 45 (73%)
Sex
Men 53 (88%) 51 (82%)
Women 7 (12%) 11 (18%)
Primary race
White 59 (98%) 61 (98%)
Other 1 (2%) 1 (2%)
Enrolment country
Germany 21 (35%) 25 (40%)
France 13 (22%) 15 (24%)
Italy 11 (18%) 9 (15%)
Other* 15 (25%) 13 (21%)
Mean weight, kg 85·59 (14·33) 84·70 (16·16)
Supplemental oxygen use at baseline
Yes 2 (3%) 8 (13%)
No 58 (97%) 54 (87%)
HRCT diagnosis
UIP pattern 43 (72%) 45 (73%)
Possible UIP pattern 17 (28%) 16 (26%)
Inconsistent with UIP pattern 0 1 (2%)
Lung biopsy 16 (27%) 26 (42%)
UIP pattern 13 (22%) 19 (31%)
Possible or probable UIP pattern 3 (5%) 4 (6%)
Unclassifiable fibrosis 0 1 (2%)
Unknown 0 2 (3%)
Bronchoalveolar lavage 32 (53%) 33 (53%)
Mean FVC volume, L 2·79 (0·55) 2·74 (0·60)
Mean FVC, % predicted 68·76 (10·14) 69·33 (11·08)
FVC <50% 1 (2%) 1 (2%)
Mean haemoglobin-corrected DLCO, % predicted 42·27 (10·19) 42·17 (9·33)
DLCO <35% 16 (27%) 17 (27%)
Mean UCSD-SOBQ 35·65 (18·18) 39·33 (27·68)
Mean 6MWD, m 439·6 (99·1) 436·2 (85·0)
Mean Borg Scale of Perceived Exertion score
Pre-walk 0·59 (0·93) 0·96 (1·34)
Post-walk 3·07 (2·21) 3·35 (2·34)

* UK (8%), Denmark (6%), Belgium (5%), Sweden (3%), and Austria (1%).

Data are n (%) or mean (SD). 6MWD=6 min walk distance. DLCO=carbon monoxide diffusing capacity of the lungs. FVC=forced vital capacity. HRCT=high-resolution CT. UCSD-SOBQ=University of California San Diego Shortness of Breath Questionnaire. UIP=usual interstitial pneumonia.

Of the 122 patients who received study drug, 52 patients in the acetylcysteine group and 55 patients in the placebo group completed the study (figure 1). All patients received pirfenidone before randomisation. The median duration of previous pirfenidone exposure was 25 weeks (range 6–122 weeks) in the acetylcysteine group and 29 weeks (range 8–132 weeks) in the placebo group (one patient in the acetylcysteine group was included in the study before they had received 8 weeks of pirfenidone but remained in the study and was included in all analyses).

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Figure 1 Trial profilePI=principal investigator. *One patient in the acetylcysteine treatment group withdrew from the study due to PI discretion before receiving study medication and was excluded from the modified intention-to-treat population. †Patient withdrawn by PI due to photosensitivity reaction caused by pirfenidone. ‡Patient withdrawn by study funder due to patient non-compliance. §One patient discontinued due to an adverse event and subsequently died more than 28 days after the last dose of study drug. ¶One of the deaths occurred more than 28 days after the last dose of study drug.

Overall, 96 patients (79%) reported 322 treatment-emergent adverse events, most of which were mild or moderate and considered unrelated to study treatment (table 2). Dose reductions of study treatment (acetylcysteine or placebo) occurred in three patients in the acetylcysteine group and three patients in the placebo group. Dose increases of study treatment (acetylcysteine or placebo) occurred in two patients in the placebo group and no patients in the acetylcysteine group.

Table 2 Summary of treatment-emergent adverse events

Pirfenidone plus acetylcysteine (n=60) Pirfenidone plus placebo (n=62)
At least one adverse event 46 (77%) 50 (81%)
Adverse events related to study medication 17 (28%) 16 (26%)
Adverse events by highest intensity
Mild 17 (28%) 19 (31%)
Moderate 25 (42%) 28 (45%)
Severe* 3 (5%) 2 (3%)
Life-threatening 1 (2%) 1 (2%)
Severe adverse events*
Back pain 1 (2%) 0
Intervertebral disc protrusion 1 (2%) 0
Diarrhoea 1 (2%) 0
Sinusitis 1 (2%) 0
Headache 1 (2%) 0
Hypertension 1 (2%) 0
Forearm fracture 0 1 (2%)
Aortic aneurysm 0 1 (2%)
Life-threatening adverse events
Malignant lung neoplasm 1 (2%) 0
Worsening IPF 0 1 (2%)
Serious adverse events 3 (5%) 4 (6%)
Dyspnoea 1 (2%) 0
Headache 1 (2%) 0
Hypertension 1 (2%) 0
Intervertebral disc protrusion 1 (2%) 0
Malignant lung neoplasm 1 (2%) 0
Aortic aneurysm 0 1 (2%)
Contusion 0 1 (2%)
Forearm fracture 0 1 (2%)
Worsening IPF 0 1 (2%)
Discontinuation of study treatment due to adverse event 4 (7%) 3 (5%)
Death 1 (2%) 3 (5%)§
Treatment-emergent adverse events reported in ≥5% of patients overall
Cough 8 (13%) 7 (11%)
Photosensitivity reaction 8 (13%) 1 (2%)
Nasopharyngitis 7 (12%) 7 (11%)
Diarrhoea 6 (10%) 9 (15%)
Nausea 4 (7%) 5 (8%)
Dyspnoea 4 (7%) 4 (6%)
Bronchitis 4 (7%) 3 (5%)
Upper respiratory tract infection 3 (5%) 5 (8%)

* Patients may have experienced more than one adverse event classified as severe.

Patients may have experienced more than one adverse event classified as serious.

One patient discontinued the study due to an adverse event but continued the study follow-up and was counted as having completed the study.

§ Two of the three deaths occurred >28 days after the last dose of study treatment.

p=0·016.

Patients were counted once within each preferred term. All investigator adverse event terms were coded using Medical Dictionary for Regulatory Activities version 11. IPF=idiopathic pulmonary fibrosis.

Of the treatment-emergent adverse events reported by at least 5% of patients overall (table 2), photosensitivity was reported by more patients in the acetylcysteine group than the placebo group (13% vs 2%; difference 11·7%; 95% CI 2·6–20·9, p=0·016). The higher incidence of photosensitivity reactions in the acetylcysteine group could not be explained by location (eg, higher ultraviolet exposure in southern vs northern Europe), a seasonal effect, or use of concomitant medications prone to cause photosensitivity reactions (data not shown). Cardiac adverse events were reported by one patient receiving acetylcysteine (atrial fibrillation) and by two patients receiving placebo (arrhythmia and atrial fibrillation). Ten severe or life-threatening treatment-emergent adverse events were reported by seven patients (table 2). Only one severe adverse event of diarrhoea reported in the acetylcysteine group was considered to be related to treatment and this patient also discontinued the study (acetylcysteine and pirfenidone) due to this event. A further three patients discontinued acetylcysteine and pirfenidone due to nausea (considered related to treatment), rash (considered related to treatment), and photosensitivity (not related). Three patients discontinued placebo and pirfenidone: one due to nausea (considered related to treatment), one due to bronchitis (not related and patient completed follow-up), and one due to anxiety, cough, and worsening IPF (none related to treatment).

Seven patients experienced serious treatment-emergent adverse events (table 2). None were considered related to treatment. Four deaths occurred during the study but none were considered related to treatment: one patient (2%) in the acetylcysteine treatment group (n=60) died from underlying lung cancer, whereas three deaths (5%) were reported in the placebo group (n=62), all attributed to worsening IPF (two of the three deaths in the placebo group were reported more than 28 days after the last dose of study drug). Three patients in each treatment group were admitted to hospital during the study.

Exploratory analysis indicated that the mean decline from baseline percent predicted FVC to week 24 was 2·65% in the acetylcysteine group and 0·47% in the placebo group (table 3). Relative to baseline, at week 24 fewer patients in the acetylcysteine group had stable or improved percent predicted FVC (≥0% change) than in the placebo group (23% [12/52] vs 42% [24/57], respectively). Eight patients (15%) in the acetylcysteine group (n=52) and seven patients (12%) in the placebo group (n=57) had 10% or more absolute decline in percent predicted FVC or death at week 24. The change from baseline in FVC volume over time is presented in figure 2.

Table 3 Summary of exploratory disease assessments at week 24

Pirfenidone plus acetylcysteine (n=60) Pirfenidone plus placebo (n=62) Difference in change from baseline between acetylcysteine and placebo groups (95% CI; p value*)
Percent predicted FVC, %
Number of patients 51 55 ..
Mean (SD) 66·16 (11·46) 69·32 (13·92) ..
Mean change from baseline −2·65 −0·47 −2·18 (−4·23 to −0·13; 0·20)
FVC, L
Number of patients 51 55 ..
Mean (SD) 2·71 (0·572) 2·73 (0·654) ..
Mean change from baseline −0·112 −0·027 −0·085 (−0·167 to −0·003; 0·14)
Percent predicted DLCO, %
Number of patients 45 54 ..
Mean (SD) 40·41 (10·26) 39·92 (10·13) ..
Mean change from baseline −2·13 −2·02 −0·11 (−2·44 to 2·22; 0·73)
6MWD, m
Number of patients 52 55 ..
Mean (SD) 433·4 (108·99) 430 (98·34) ..
Mean change from baseline −4·3 −11·7 7·4 (−16·24 to 31·06; 0·54)
Borg Scale of Perceived Exertion score
Number of patients 52 55 ..
Mean pre-walk (SD) 0·91 (0·99) 1·10 (1·30) ..
Mean post-walk (SD) 3·18 (1·68) 3·57 (2·04) ..
Difference (post-walk minus pre-walk) 2·27 (1·64) 2·47 (1·77) ..
Mean change in difference from baseline −0·08§ −0·03 −0·05 (−0·75 to 0·65; 0·64)
UCSD-SOBQ score
Number of patients 48 54 ..
Mean (SD) 40·06 (22·79) 44·41 (27·95) ..
Mean change from baseline 7·1 5·79 1·31 (−5·02 to 7·64; 0·85)

* p value calculated from rank ANCOVA.

n=50.

Score ranges from 0 (no shortness of breath) to 10 (very, very severe shortness of breath).

§ n=51.

n=47.

6MWD=6 min walk distance. DLCO=carbon monoxide diffusing capacity of the lungs. FVC=forced vital capacity. UCSD-SOBQ=University of California San Diego Shortness of Breath Questionnaire.

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Figure 2 Exploratory efficacy outcomesFigure shows mean (SE) change in FVC volume over time (A), and adjusted rate of decline in FVC volume at 6 months (B). FVC=forced vital capacity. DLCO=carbon monoxide diffusing capacity of the lungs. *From slope analysis with adjustment for age, sex, and height. †Pirfenidone plus acetylcysteine, n=17; pirfenidone plus placebo; n=18.

A post-hoc slope analysis gave an adjusted rate of decline in FVC of 125·6 mL/6 months in the acetylcysteine group, compared with 34·3 mL/6 months in the placebo group (difference −91·3 mL; 95% CI −174·4 to −8·3; p=0·031; figure 2). The adjusted rate of FVC decline for patients with more advanced disease at baseline (FVC <50%, DLCO <35%, or both) was greater than in patients with less advanced disease at baseline (figure 2).

Changes in percent-predicted DLCO were similar between the two treatment groups at week 24 (table 3). The mean reduction at week 24 from baseline in 6MWD was 4·3 m in the acetylcysteine group and 11·7 m in the placebo group (table 3). Similar findings were noted between the acetylcysteine and placebo groups in the proportion of patients experiencing at least a 50 m decline in 6MWD or death (20% [10/51] vs 19% [11/57]), or in the proportion of patients with no change in 6MWD (53% [27/51] vs 53% [30/57]) at week 24. Pre-walk and post-walk Borg scores were similar between the two treatment groups at week 24 (table 3). Pre-walk and post-walk oxygen saturation levels were also similar between the two treatment groups (data not shown). The mean changes from baseline in UCSD-SOBQ scores at week 24 were 7·1 in the acetylcysteine group and 5·8 in the placebo group (table 3). The appendix shows change from baseline values for lung-function parameters at week 12.

Discussion

In this randomised, placebo-controlled trial, the combination of pirfenidone and oral acetylcysteine at a dose of 1800 mg/day was generally well tolerated in patients with IPF. The safety profile of the acetylcysteine and pirfenidone combination was similar to that of pirfenidone alone, except for an increased incidence in photosensitivity. This result differs from the findings of an observational study of real-world use of pirfenidone in Germany. Although no difference was reported in the incidence of photosensitivity between treatment groups in the study from Germany, an increased occurrence of adverse events and treatment discontinuations due to adverse events was observed in patients receiving combination therapy versus pirfenidone alone.20 However, corticosteroids and their associated adverse events22 could have contributed to the result from this study. Furthermore, patients receiving combination therapy in the German study had decreased lung function at baseline compared with patients receiving monotherapy, suggesting that combination therapy might have been initiated in patients with more advanced IPF.20

Although the frequency and type of adverse events in the acetylcysteine and placebo groups were similar overall in the PANORAMA study, photosensitivity occurred more frequently in patients treated with acetylcysteine. Photosensitivity is a known adverse event associated with pirfenidone, as observed in the CAPACITY and ASCEND trials,11 and 12 but previous studies have not reported photosensitivity to be a common adverse event with acetylcysteine.14, 16, and 21 Further analysis of the available data did not provide an explanation for the effect observed in PANORAMA. Information on the profession or leisure activities of the patients with photosensitivity was not collected, limiting our ability to determine if the patients affected by photosensitivity routinely spent time outdoors. In view of the small size of the study, and the fact that there is no known biochemical rationale whereby acetylcysteine could cause photosensitivity or increase photosensitivity reactions caused by pirfenidone, it is possible that this effect occurred by chance.

The frequency of cardiac adverse events was not increased in the acetylcysteine treatment group relative to the placebo group in this study, even though more patients had cardiac comorbidities at baseline in the acetylcysteine group than in the placebo group. This is notable because the PANTHER study16 reported a slightly increased risk of cardiac events in patients treated with acetylcysteine versus placebo.

Although our safety data do not suggest that acetylcysteine affects the tolerability of pirfenidone, findings from our exploratory efficacy analyses argue against the use of acetylcysteine in combination with pirfenidone. Contrary to findings from a study of inhaled acetylcysteine in combination with pirfenidone,21 exploratory efficacy endpoints in PANORAMA provided no evidence to suggest that oral acetylcysteine has a clinical benefit when added to pirfenidone for the treatment of IPF. Indeed, analysis of the decline in FVC over 24 weeks suggested that patients treated with acetylcysteine experienced a greater decline in lung function than those treated with placebo. This result was most apparent in patients with FVC less than 50% or DLCO less than 35% at baseline, although the reason for the greater effect in patients with more severe disease is unclear. However, the reliability of the observed effect of acetylcysteine on FVC is questionable given the lack of correlation with other efficacy endpoints. The mean change from baseline in percent predicted DLCO was similar between treatment groups at week 24, and the mean change in 6MWD was below the minimal clinically important difference of between 24 m and 45 m identified by du Bois and colleagues23 in their validation of the 6MWD in IPF. Additionally, the small study population size and the short duration of the study limits the conclusions that can be drawn from these data.

Previous clinical data for acetylcysteine in IPF have given varying results. The addition of acetylcysteine to prednisone and azathioprine was associated with improved pulmonary function in the IFIGENIA trial;14 however, the triple combination group was stopped early in the more recent PANTHER study15 due to an increased risk of harm. The acetylcysteine monotherapy group continued but reported no benefit in terms of pulmonary function or mortality outcomes in patients with IPF.16 An analysis of data from the PANTHER study by Oldham and colleagues17 suggested that acetylcysteine could be beneficial in patients carrying the TOLLIP rs3750920 T/T genotype, but may be associated with harm in patients carrying the C/C genotype, possibly by reducing the defence against infection and thereby amplifying IPF progression. These results provide a potential mechanism whereby pirfenidone provides the benefit of acetylcysteine observed in patients with a T/T TOLLIP genotype in the Oldham analysis but does not prevent the harm of acetylcysteine in patients with the C/C genotype, resulting in a negative effect on FVC. However, these results are hypothesis generating and prospective trials are required to assess the safety and efficacy of acetylcysteine in patients with the T/T TOLLIP genotype. Patients in PANORAMA did not provide samples for genotype analysis so we were unable to replicate the Oldham analysis in patients on combination treatment.

In conclusion, the findings from the PANORAMA study suggest that the addition of acetylcysteine to pirfenidone does not substantially alter the tolerability profile of pirfenidone, although the incidence of photosensitivity should be closely monitored in patients receiving combination treatment. Results from exploratory efficacy endpoints showing that patients treated with acetylcysteine experienced a greater decline in FVC than those treated with placebo suggest that acetylcysteine is unlikely to have a beneficial role in IPF when combined with pirfenidone and raise the distinct possibility that the combination might be harmful in patients with IPF.

Contributors

JBeh, BC, JBec, and CA contributed to the design of the study. JBeh, EB, BC, AG, HO, CMS, AW, WW, DK, MK, BW, and CA contributed to the execution of the study by enrolling patients. JBeh, EB, BC, AG, HO, CMS, AW, WW, DK, MK, BW, C-YL, JBec, and CA contributed to interpretation of the study. JBeh, BC, C-YL, and JBec contributed to the study analysis. JBeh and JBec contributed to writing the clinical study report. All authors were involved in drafting and revising this report, and provided final approval of the version to be published. All authors vouch for the accuracy of the content included in the final report.

Declaration of interests

JBeh received fees for chairing the steering committee of the PANORAMA trial from InterMune/Roche. He has also received fees for lectures and consulting from InterMune/Roche, Boehringer Ingelheim, Actelion, Bayer, and GlaxoSmithKline, and fees from Gilead for consulting and being a member of a data and safety monitoring board, and research funding from InterMune/Roche. EB and CMS received research funding and compensation for lectures and consulting from InterMune/Roche. BC received research grants from InterMune/Roche, Boehringer Ingelheim, Medimmune, and LVL, fees from InterMune/Roche, Boehringer Ingelheim, and Sanofi, and non-financial support from InterMune/Roche, Boehringer Ingelheim, and LVL. AG received funding for participation in the PANORAMA trial from InterMune/Roche. He also received research grants from InterMune/Roche and fees for lectures and consulting from InterMune/Roche and Boehringer Ingelheim. HO received grants from Actelion, Boehringer Ingelheim, and Roche, fees from Actelion, Bayer, Boehringer Ingelheim, Novartis, GlaxoSmithKline, Menarini, AstraZeneca, and Merck Sharp & Dohme, and non-financial support from Actelion, Bayer, Boehringer Ingelheim, Novartis, and Menarini. AW received fees for lectures and/or consulting from InterMune/Roche, Boehringer Ingelheim, Bayer, Gilead, and Chiesi. DK received funding for participation in the PANORAMA trial from InterMune/Roche. He also received fees and non-financial support for lectures, consulting and attending meetings from InterMune/Roche and Boehringer Ingelheim. MK and BW received research funding and compensation for lectures and consulting from InterMune/Roche and Boehringer Ingelheim. C-YL is an employee of Roche-Genentech. JBec is a former employee (as of July 1, 2015) of InterMune International AG, Muttenz, Switzerland. CA received compensation for lectures and consulting from InterMune/Roche. WW declares no competing interests.

Acknowledgments

Study monitoring services were provided by Florence Longueville and colleagues at Theorem Clinical Research. We thank Helen Tang, formerly of InterMune, for her work on the statistical analyses for the PANORAMA study. This study was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London. Medical writing support was provided by Catherine Stanton on behalf of Complete Medical Communication, funded by Roche.

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References

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Footnotes

a Department of Internal Medicine V, Ludwig-Maximilian University of Munich, Munich, Germany

b Asklepios Clinic Gauting, Member of the German Center for Lung Research, Germany

c Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark

d AP-HP, Hôpital Bichat, Service de Pneumologie A, DHU FIRE, Université Paris Diderot, Paris, France

e University of Giessen, Agaplesion Lung Clinic Greifenstein, Member of the German Center for Lung Research, Giessen, Germany

f Department of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria

g Department of Medicine, Karolinska University Hospital Solna, and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

h Interstitial Lung Disease Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK

i Department of Respiratory Medicine, University Hospitals Leuven, Leuven, Belgium

j Department of Internal Medicine/Pulmonology, Fachkrankenhaus Coswig, Coswig, Germany

k Pneumology and Respiratory Critical Care Medicine, Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, Member of the German Center for Lung Research, Heidelberg, Germany

l CHU, Service de Pneumologie et Immuno-allergologie, Hôpital Albert Calmette, Lille, France

m Genentech, San Francisco, CA, USA

n InterMune International AG, Muttenz, Switzerland

o Department of Clinical and Biological Sciences, Interstitial and Rare Diseases Unit, University of Turin, Turin, Italy

* Correspondence to: Prof Jürgen Behr, Klinikum der Ludwig-Maximilian-Universität München, Comprehensive Pneumology Center, 81377 München, Germany

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