Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease lacking effective treatment.
Objectives: To determine the effects of bosentan on exercise capacity and time to disease progression in patients with IPF.
Methods: In a double-blind, multicenter trial, patients with IPF were randomized to receive oral bosentan 62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter, or placebo, for 12 months or longer. The primary efficacy endpoint was change from baseline up to Month 12 in exercise capacity, as measured by a modified six-minute-walk test. Secondary endpoints were time to death or disease progression (worsening pulmonary function tests [PFTs] or acute decompensation), change in PFT scores, and quality of life (QOL) assessed using Short-Form 36 and St. George's Respiratory Questionnaire.
Measurements and Main Results: A total of 158 patients randomly received bosentan (n = 74) or placebo (n = 84). Bosentan showed no superiority over placebo in six-minute-walk distance (6MWD) up to Month 12, the primary efficacy endpoint. A trend in favor of bosentan was observed in the secondary endpoint of time to death or disease progression (hazard ratio [HR], 0.613; 95% confidence interval [CI], 0.328−1.144; P = 0.119), which was more pronounced in a patient subgroup diagnosed using surgical lung biopsy (post hoc analysis; HR, 0.315; 95% CI, 0.126−0.789; P = 0.009). Changes from baseline up to Month 12 in assessments of dyspnea and QOL favored treatment with bosentan. No unexpected adverse events were reported.
Conclusions: Bosentan treatment in patients with IPF did not show superiority over placebo on 6MWD. A trend in delayed time to death or disease progression, and improvement in QOL, was observed with bosentan. The more pronounced treatment effect in patients with biopsy-proven IPF warrants further investigation.
Clinical trial registered with www.clinicaltrials.gov (NCT 00071461).
Idiopathic pulmonary fibrosis (IPF) is a progressive disease that affects quality of life. The predominant symptom is progressive dyspnea, which occurs first on exercise and then at rest. Median survival following biopsy-confirmed IPF is less than 3 years.
The BUILD-1 study was a large, randomized, multinational, double-blind, placebo-controlled trial in a well-defined population of patients with IPF. It is the first randomized trial to investigate the effects of an endothelin receptor antagonist in IPF.
Endothelin (ET)-1, a potent, endogenous vasoconstrictor, is implicated in the pathophysiology of pulmonary arterial hypertension (PAH) through proliferation of smooth muscle cells, inflammation, fibrosis, and endothelial dysfunction (2–7). In addition, ET-1 is a profibrotic molecule that can modulate matrix production and turnover, resulting in increased collagen synthesis and decreased interstitial collagenase production (6). Preliminary data suggest that ET-1 plays an important role in the pathogenesis of lung fibrosis. In a rat model of bleomycin-induced pulmonary fibrosis, bosentan, a dual ET receptor antagonist (ETA and ETB), was shown to reduce collagen deposition in the lungs (8). Bosentan has been shown to be an efficacious treatment for PAH, a disease characterized by progressive remodeling of the pulmonary vasculature. Consequently, we hypothesized that bosentan may influence the course of IPF through its antiinflammatory and antifibrotic effects.
The BUILD 1 (Bosentan Use in Interstitial Lung Disease) study was designed to evaluate the efficacy, safety, and tolerability of bosentan in patients with IPF. The primary objective was to evaluate the effect of bosentan on exercise capacity (six-minute-walk distance [6MWD]). Secondary objectives included investigation of the effect of bosentan on time to disease progression or death, pulmonary function tests (PFTs), dyspnea, and QOL, as well as determining its safety and tolerability in patients with IPF. Some of the results of this clinical trial have been previously reported in abstract form (9–14).
This international, prospective, double-blind, randomized, placebo-controlled, parallel group study enrolled patients with a proven diagnosis of IPF made within the last 3 years before enrollment according to American Thoracic Society/European Respiratory Society consensus guidelines (15, 16). In addition to clinical evaluation, a high-resolution computed tomography (HRCT) scan within the previous 3 months was used to demonstrate a definitive diagnosis of IPF. If the diagnosis could not be confirmed based on the HRCT scan, a surgical lung biopsy (SLB) was mandatory to determine a histopathologic diagnosis of usual interstitial pneumonia (UIP), and thus patient eligibility. Patients were included if their duration of illness was 3 months or more and they had a baseline 6MWD between 150 and 499 m. Women of child-bearing age were required to use a reliable method of contraception.
Patients were excluded if they had interstitial lung disease (ILD) due to conditions other than IPF, severe restrictive lung disease (FVC < 50% predicted [formula reported in Reference 17]; diffusing capacity for carbon monoxide [DlCO], corrected for hemoglobin level < 30% predicted [formula reported in Reference 18]; or RV ⩾ 120% [formula reported in Reference 19]), obstructive lung disease (FEV1/FVC < 65%), echocardiographic evidence of severe pulmonary hypertension (systolic pulmonary pressure ⩾ 50 mm Hg or tricuspid regurgitation velocity ⩾ 3.2 m/s), severe congestive heart failure, or a terminal (expected survival < 1 yr) concomitant illness. Other exclusion criteria included an FVC of 90% predicted or greater, resting arterial oxygen pressure (PaO2) of less than 55 mm Hg (sea level) or 50 mm Hg (above 1,400 m), hemoglobin concentration les than 75% of the lower limit of normal, systolic blood pressure less than 85 mm Hg, moderate to severe hepatic impairment, and serum creatinine of 2.5 mg/dl or greater. Concomitant treatment with immunosuppressive, cytotoxic drugs or other investigational agents was not allowed, except for stable corticosteroid therapy of 15 mg or less of prednisone or equivalent. Other prohibited medications included calcineurin inhibitors, fluconazole, and glyburide, due to potential interactions with bosentan.
All patients gave written, informed consent to participate in the study, which was approved by the appropriate independent ethics committees or institutional review boards and conducted in accordance with the principles of the Declaration of Helsinki and local laws and guidelines for good clinical practice.
This study was performed in 29 centers in Europe (Germany, France, Italy, Switzerland, and United Kingdom), the United States, Canada, and Israel. Within 4 weeks of screening, eligible patients were randomized 1:1 to oral bosentan 62.5 mg twice daily for 4 weeks, uptitrated to bosentan 125 mg twice daily thereafter (target dose), or matching placebo. Patients unable to tolerate the target dose could be maintained on bosentan 62.5 mg twice daily. Patients completing 12 months of double-blind therapy continued treatment until end of study, which was when the last patient randomized to study medication and not prematurely discontinued completed a full 12 months of treatment. Results at Month 12, or earlier if patient discontinued prematurely (up to Month 12), are reported here.
Patients were assessed at baseline and after 3, 6, 9, and 12 months of therapy (or earlier if they discontinued prematurely), and again at the end of the study. Baseline assessments included physical examination, vital signs, ECG and echocardiography, dyspnea and QOL questionnaires, oxygen saturation by pulse oximetry (SpO2) (Nellcor N-595; Pleasanton, CA), and 6MWD. The 6MWD was measured without supplemental oxygen using a modified six-minute-walk test (6MWT), conducted in accordance with American Thoracic Society guidelines (20), but terminated prematurely if SpO2 fell below 80%. The 6MWD, SpO2, and Borg dyspnea index were reassessed at the 3-, 6-, and 9-month visits and, together with full PFTs and laboratory tests, at Month 12. These assessments were repeated in patients at the end of study.
The primary endpoint of the study was change in 6MWD from baseline up to Month 12. Other endpoints included the following:
Time to disease progression or death up to Month 12. Disease progression was defined as worsening PFTs or acute decompensation (unexplained rapid deterioration over 4 wk with increased dyspnea requiring hospitalization and oxygen supplementation ⩾ 5 L/min to maintain a resting oxygen saturation [arterial blood gas; SaO2] ⩾ 90% or PaO2 ⩾ 55 mm Hg [sea level] or 50 mm Hg [above 1,400 m]). For the efficacy analysis, vital status was recorded at Month 12 or within 15 days after study medication discontinuation, regardless of whether the patient was on or off study drug.
PFT scores up to Month 12, defined as worsened, meeting two of the following three criteria: decrease from baseline ⩾ 10% in % predicted FVC; decrease from baseline of ⩾ 15% in % predicted DlCO; decrease from baseline of ⩾ 4% in SaO2 at rest or increase from baseline ⩾ 8 mm Hg in alveolar–arterial oxygen gradient [P(a–a)o2]; improved (improvement of the same magnitude in two out of these three criteria); or stable (neither worsened nor improved).
Dyspnea scores at Month 6 and Month 12. Dyspnea was measured at rest, before the 6MWT, by the baseline dyspnea index (BDI) (21) and immediately after the 6MWT by the Borg dyspnea index. Each component of the BDI (functional impairment, magnitude of task, magnitude of effort) was scored from 0 (severe) to 4 (unimpaired). Thus, the maximum score ranged from 0 to 12. The change in dyspnea from baseline was measured at rest, before the 6MWT, by the transition dyspnea index (TDI), and ranged from −3 (major deterioration) to +3 (major improvement) or −9 to +9 for all three components. The Borg dyspnea index was scored on a scale of 0 (no dyspnea) to 10 (maximum dyspnea).
QOL scores at Month 6 and Month 12. QOL was assessed using the Short-Form 36 (SF-36) health survey, a nonspecific, validated (22) health status survey, and the St. George's Respiratory Questionnaire (SGRQ), a self-administered respiratory-specific instrument validated in ILD (23). The SF-36 health survey assessed QOL in eight domains, each scored from 0 (maximum impairment) to 100 (no impairment). The SGRQ evaluates the patient's ability to perform 50 activities of daily living grouped into three components: symptoms, activity, and impact. Scores of each component and the total score are on a 100-point scale (0 = no impairment).
All randomized patients who received at least one dose of study medication and had at least one postbaseline safety measurement were included in the safety analysis (safety set). Liver function tests were performed at monthly intervals. All serious adverse events (SAEs), including deaths, were monitored for up to 28 days after end of treatment.
The sample size calculation was based on the primary endpoint. The Wilcoxon rank sum test was used to test the null hypothesis of no difference between treatment groups for change in 6MWD from baseline to up to 12 months. The study was powered to detect a mean difference of 45 m assuming normal distributions with a common standard deviation of 75 m. Acceptable probabilities for type I (two-sided) and type II errors were 0.05 and 0.10, respectively (90% power). A sample size of 132 (66 patients per treatment group) was required to reject the null hypothesis, if the above-mentioned alternative hypothesis was true, with the requisite probabilities of error. Analysis of the primary endpoint was based on the all-treated set, comprising all randomized patients who had received study medication and had at least one valid postbaseline assessment for the primary efficacy endpoint. The median placebo-corrected treatment effect and its 95% two-sided confidence interval (CI) were estimated using Hodges-Lehmann method. For patients with missing values, the analysis was performed with the last observation carried forward; however, an imputed value of zero was given in case of disease progression or death. Imputation values were identified before breaking treatment blinding.
Secondary and exploratory endpoints were summarized descriptively for the all-treated set. Statistical tests of treatment comparison were for exploratory purposes, as no formal hypothesis testing for these comparisons was planned. No correction for multiple testing was performed.
Kaplan-Meier estimates of the survivor function at different time points were presented together with the 95% CI calculated using Greenwood's formula. The log-rank test was used to compare treatments for time-to-event distribution. The hazard ratio (HR) of the bosentan group to placebo was calculated together with its 95% CI by means of Cox's modeling using only the treatment as an independent variable.
Patients who underwent SLB for diagnosis of IPF were identified as a subpopulation of interest before revealing the treatment allocation. The effect of bosentan in this specific subpopulation was explored in a post hoc analysis.
A total of 154 of the 158 randomized patients were included in the all-treated set (bosentan, n = 71; placebo, n = 83). Treatment groups were generally well matched with regard to demographics and baseline characteristics (Table 1), although the bosentan group had slightly worse baseline FVC, more patients on prednisone and supplemental oxygen, and five patients awaiting lung transplantation compared with none in the placebo group.
Characteristic | Bosentan (n = 71) | Placebo (n = 83) |
|---|---|---|
| Male, n (%) | 49 (69.0) | 63 (75.9) |
| Age, yr, mean ± SD (range) | 65.3 ± 8.4 (38–80) | 65.1 ± 9.1 (46–82) |
| IPF medical status | ||
| Duration of symptoms, yr, mean ± SD | 2.4 ± 2.1 | 2.5 ± 1.7 |
| Duration since diagnosis, yr, mean ± SD | 1.2 ± 1.2 | 1.1 ± 1.0 |
| Underwent SLB, n (%) | 49 (69.0) | 50 (60.2) |
| Digital clubbing, n (%) | 15 (21.4) | 25 (30.1) |
| Smoking status | ||
| Current smokers, % | 2.8 | 1.2 |
| Transplantation list, n (%) | 5 (7.0) | None |
| Relevant concomitant medications at study baseline, n (%)* | ||
| Prednisone | 19 (25.7) | 11 (13.1) |
| Oxygen | 17 (23.0) | 13 (15.5) |
| Exercise test, mean ± SD | ||
| 6MWD, m | 375 ± 92 | 372 ± 74 |
| Borg dyspnea index | 2.5 ± 1.4 | 2.5 ± 1.7 |
| Pulmonary function tests, mean ± SD | ||
| FVC, % predicted | 65.9 ± 10.5 | 69.5 ± 12.6 |
| FEV1, % predicted | 78.8 ± 14.3 | 81.8 ± 13.8 |
| DlCO, % predicted | 42.3 ± 9.5 | 41.4 ± 9.5 |
| Arterial blood gas, mean ± SD | ||
| P(a–a)o2 at rest, mm Hg | 20.9 ± 11.8 | 18.2 ± 11.5 |
| Pulse oximetry, mean ± SD | ||
| SpO2 at rest, % points | 96.6 ± 2.3 | 96.8 ± 2.5 |
In total, 68 and 60% of patients in the bosentan and placebo groups, respectively, had undergone SLB at diagnosis. Patients with biopsy-proven IPF had similar duration of symptoms and lung function at baseline compared with the all-treated set but tended to be younger; biopsy-proven patients had a mean age of 62.4 and 64.1 years in the bosentan and placebo groups, respectively, compared with 65.3 and 65.1 years in the all-treated population.
In total, 154 patients received at least one dose of study medication and had at least one valid postbaseline value for the primary endpoint and were included in the all-treated set (Figure 1). Of the 158 randomized patients, 49 patients discontinued study medication before Month 12, mainly due to adverse events (AEs) or disease progression (n = 39). Other reasons for discontinuation of study medication were withdrawal of consent by the patient (n = 9) and transplant (n = 1). No patient was lost to follow-up.
Exposure to study medication was similar in the two treatment groups, with a mean duration (± SD) of 54.0 ± 24.9 weeks in the bosentan group and 56.1 ± 21.0 weeks in the placebo group. The majority of patients in the bosentan and placebo groups (74.3 and 75.0%, respectively) received at least 48 weeks of treatment.
No statistically significant difference was observed between the two treatment groups (all-treated set) as measured by the modified 6MWT up to Month 12. In both groups, the 6MWD at Month 12 (primary endpoint) decreased, with a mean change from baseline of −52 m in the bosentan group and −34 m in the placebo group. The median treatment effect was −17 m (P = 0.226) (Table 2). These results include data on 33.8% (n = 25) of bosentan- and 28.6% (n = 24) of placebo-treated patients who did not complete 12 months of treatment and for whom either a last observation carried forward or an imputed value of zero was used in the analysis.
Characteristic | Bosentan (n = 71) | Placebo (n = 83) |
|---|---|---|
| Baseline, m | ||
| Mean ± SD | 375 ± 92 | 372 ± 74 |
| Median | 397 | 387 |
| Up to Month 12 (m) | ||
| Mean ± SD | 323 ± 164 | 338 ± 162 |
| Median | 390 | 369 |
| Change,* m | ||
| Mean ± SD | −52 ± 121 | −34 ± 127 |
| Median | −23 | −9 |
| Treatment effect | ||
| Mean ± SD | −18 ± 20 | |
| Median | −17 | |
| P value | 0.226 |
Up to Month 12, the combined incidence of disease progression or death was 22.5% (n = 16) in the bosentan group and 36.1% (n = 30) in the placebo group. This corresponded to a relative risk reduction of 38% (95% CI, −5 to 63%; P = 0.078). A positive trend in favor of bosentan was observed in the secondary efficacy endpoint of time to disease progression or death up to Month 12 (HR, 0.613; 95% CI, 0.328−1.144; P = 0.119; Figure 2). These results were driven by the difference in the worsening of FVC and DlCO, as the number of deaths up to Month 12 in each group of patients on study treatment was the same (n = 3) (i.e., death occurring within 15 d of the end of study treatment). There were three cases of acute decompensation of IPF in the placebo group (3.6%) and one case in the bosentan group (1.4%).
Figure 2. Kaplan-Meier estimates of time to disease progression or death up to Month 12 in all-treated set. CI = confidence interval.
[More] [Minimize]There were no differences in the proportion of patients with improved or stable PFT scores, and few patients overall had improved PFT scores (n = 3) (Table 3). Mean absolute changes from baseline in percent-predicted FVC up to Month 12 were −6.4 and −7.7% in the bosentan and placebo groups, respectively. Corresponding changes from baseline in percent-predicted DlCO were −4.3 and −5.8% in the bosentan and placebo groups, respectively. No clinically relevant differences were observed between treatment groups with respect to A-a Po2 or SaO2, providing little evidence to suggest that changes in blood gas parameters were a major contributor to worsening PFTs in either treatment arm.
Bosentan (n = 71) | Placebo (n = 83) | |
|---|---|---|
| Worsened | 16 (22.5%) | 30 (36.1%) |
| 95% confidence limits | 13.5–34.0% | 25.9–47.4% |
| Treatment effect | ||
| Relative risk | 0.62 | |
| 95% confidence limits | 0.37–1.05 | |
| P value* | 0.0784 | |
| Improved | 2 (2.8%) | 1 (1.2%) |
| 95% confidence limits | 0.3–9.8% | 0.0–6.5% |
| Treatment effect | ||
| Relative risk | 2.34 | |
| 95% confidence limits | 0.22–25.25 | |
| P value* | 0.5952 |
Shortness of breath, assessed at the end of the 6MWT using the Borg dyspnea index, was more pronounced in the placebo group compared with the bosentan group up to Month 12 (median treatment effect, −0.5; P = 0.071). Patients' perception of dyspnea assessed with the TDI mirrored these findings. From similar mean BDI scores at baseline, TDI total scores worsened in both treatment groups over time. The TDIs at Month 6 were −0.6 and −1.9 in the bosentan and placebo groups, respectively, and −1.7 and −2.6 in the bosentan and placebo groups, respectively, at Month 12. The worsening of the TDI was significantly smaller for patients treated with bosentan than for patients treated with placebo (P = 0.016) at Month 6, but not at Month 12 (P = 0.292).
When asked to rate their general health status during the study period compared with 1 year prior, 42.4% (n = 28) of bosentan-treated patients had an improved SF-36 health transition score compared with 28.4% (n = 23) of placebo recipients—a relative risk of improvement in favor of bosentan of 1.49 (95% CI, 0.96–2.33; P = 0.084). Changes in seven of the eight domains of the SF-36 survey up to Month 12 were in favor of bosentan treatment, with a significant treatment effect in favor of bosentan observed in the domain “role emotional” (P = 0.032).
Mean changes from baseline in SGRQ scores showed a similar pattern. Total SGRQ score at baseline in the bosentan group (mean ± SD, 45.7 ± 18.1) was similar to that in the placebo group (mean ± SD, 45.2 ± 19). Up to Month 6, the total score in the bosentan group remained almost unchanged (mean ± SD, 45.0 ± 21.3), whereas it worsened in the placebo group (mean ± SD, 47.8 ± 21.7), representing a mean ± SEM treatment effect of −3.3 ± 2.6 (P = 0.034). Mean treatment differences up to Month 12 continued to favor bosentan but were smaller (data not shown).
A treatment effect in favor of bosentan was observed in the subgroup of patients who had undergone SLB to confirm diagnosis of ILD. In these patients, the combined incidence of disease progression or death was 12.2% for bosentan-treated patients and 38.0% for those who received placebo. This corresponded to a relative risk reduction of 68% (95% CI, 26–86%; P = 0.005). The Kaplan-Meier plot of time to disease progression or death up to Month 12 is shown in Figure 3. Post hoc analyses of time to death or disease progression in other subpopulations defined by age, gender, or patient location revealed a similar pattern to that seen in the total study population, with an observed treatment difference in favor of bosentan (data not shown).
Figure 3. Kaplan-Meier estimates of time to disease progression or death up to Month 12 in patients who underwent surgical lung biopsy to confirm diagnosis of idiopathic pulmonary fibrosis.
[More] [Minimize]In addition, QOL results demonstrated a more pronounced treatment effect in favor of bosentan in the SLB subgroup. For these patients, three domains of the SF-36 health transition score showed a significant treatment effect in favor of bosentan at Month 12: “physical functioning” (P = 0.041), “general health” (P = 0.012), and “role emotional” (P = 0.037). Total SGRQ scores at baseline were similar between the bosentan-treated (mean ± SD, 44.3 ± 18.0) and placebo-treated (mean ± SD, 45.9 ± 16.9) SLB subgroups. Up to Month 6, the mean total SGRQ score in the bosentan-treated subgroup remained similar to baseline (mean ± SD, 43.6 ± 18.2), but worsened in the placebo-treated subgroup (mean ± SD, 49.2 ± 21.3)—a mean ± SEM treatment effect of −7.3 ± 2.8 (P = 0.010) in favor of bosentan. Up to Month 12, the mean total SGRQ scores favored treatment with bosentan (mean ± SD, 46.1 ± 19.9) versus placebo (mean ± SD, 51.1 ± 23.7)—a mean ± SEM treatment effect of −6.6 ± 3.0 (P = 0.058).
A total of 158 randomized patients were included in the safety set (bosentan, n = 74; placebo, n = 84). Reported AEs included several respiratory AEs, which were less frequent among bosentan-treated patients compared with those who had received placebo, as follows: cough (17.6 vs. 27.4%), worsening of IPF (16.2 vs. 23.8%), and exacerbation of dyspnea (13.5 vs. 19.0%). Elevations in alanine aminotransferases were measured in 20.5 and 0.0% of bosentan- and placebo-treated patients, respectively. In all cases, they resolved with no change, decrease in dose, or treatment discontinuation without clinical sequelae. Nine bosentan-treated patients (12.2%) and no placebo-treated patients discontinued due to abnormal liver function tests, although not all patients, as per protocol, had an elevation of aminotransferase levels that required treatment discontinuation. Apart from a higher incidence of hepatic aminotransferase elevations, changes in laboratory variables from baseline were small and not clinically relevant in either treatment group. In total (up to end of study treatment), 25 (33.8%) bosentan-treated patients and 23 (27.4%) placebo-treated patients discontinued treatment because of AEs.
SAEs up to end of treatment were mainly respiratory in nature and were slightly less frequent in the bosentan group (34 SAEs in 22 patients, 29.7%) than in the placebo group (44 SAEs in 29 patients, 34.5%). In contrast to the deaths that occurred on study treatment (n = 3 in each group), the total number of deaths at 1 year, including patients who were on or off study medication or had prematurely discontinued study treatment, was eight in the placebo group and five in the bosentan group. The majority of deaths were due to IPF.
The BUILD-1 study was a large, randomized, multinational, double-blind, placebo-controlled trial in a well-defined population of patients with IPF. It is the first randomized trial to investigate the effects of an ET receptor antagonist in IPF. A previous open-label study of the safety of bosentan in 12 patients with IPF reported that long-term bosentan therapy was well tolerated, with AEs similar to those reported in studies with patients with PAH (24).
Our study was designed and powered to investigate the effect of bosentan on exercise capacity, by evaluating the change in 6MWD from baseline up to Month 12 using a modified 6MWT. Although bosentan did not show an improvement over placebo with respect to 6MWD, several clinically relevant results in secondary and exploratory endpoints suggest beneficial treatment effects at Months 6 and 12. The most clinically important finding in this study is that treatment with bosentan showed a trend to delayed time to death or disease progression, a predefined secondary endpoint. This treatment effect was significant in the subset of patients who underwent SLB for confirmation of diagnosis. Results for this predefined secondary endpoint in the overall population showed consistent trends in favor of bosentan, both overall and in its PFT components. FVC and DlCO at baseline, as well as changes in these parameters over time, have been shown to be good predictors of survival in patients with IPF (25, 26).
Treatment with bosentan was generally well tolerated by patients in this study, with a safety profile consistent with that seen in patients with PAH (27, 28). In this study, 12.2% of bosentan-treated patients discontinued treatment due to abnormal liver function tests, although not all of these patients had an elevation of aminotransferase levels that required treatment discontinuation. All aminotransferase elevations were asymptomatic and resolved or improved without clinical sequelae after dose reduction or treatment discontinuation.
In the patients who presented with an atypical HRCT scan, SLB was performed to confirm diagnosis. The subgroup of patients who underwent SLB had a more pronounced treatment effect in regard to the combined incidence of disease progression or death and improvements in QOL. This suggests that treatment with bosentan may be of particular benefit to this subgroup of patients.
Results of other secondary efficacy endpoints also provide evidence to suggest beneficial effects with bosentan treatment. Treatment effects with bosentan on both dyspnea (TDI) and QOL (SGRQ) were significant at Month 6, with a favorable trend observed up to Month 12. QOL is known to be impaired in patients with IPF (29, 30), and across all but one domain of the SF-36 QOL instrument, results trended in favor of bosentan, with a significant effect on the role-emotional domain. No other study for IPF to date has shown positive treatment effects on QOL.
There are a number of limitations with the BUILD-1 study. The 6WMT has potential confounders and its sensitivity to change can be uncertain (31–34). The 6MWT may not be ideally suited for assessing either disease progression or response to treatment with bosentan in patients with IPF. In addition, use of a modified 6MWT makes comparison with other studies difficult. Second, there were several small imbalances between the treatment groups at baseline to suggest that patients in the bosentan treatment group had more severe disease; baseline PFT values were slightly worse, as was time to desaturation to 88% during the 6MWT (data not shown); more patients in the bosentan group were on oxygen and more were listed for lung transplantation. These differences at baseline may have influenced outcome in the 6MWT. In addition, it is important to note that diagnosis of IPF/UIP is difficult. SLBs were read by local pathologists and not by a core lab. SLBs were read centrally in a post hoc analysis (86 patients) and showed that 64 patients (74%) have a confirmed UIP diagnosis (data not shown). Finally, although a treatment effect in favor of bosentan was observed for the clinically relevant secondary endpoint of time to disease progression or death, the study was not powered to detect a significant difference between treatment groups with respect to this important measurement.
In this study, bosentan treatment in patients with IPF did not show superiority over placebo on change in 6MWD from baseline up to Month 12, the primary endpoint. However, bosentan was well tolerated and the observed clinically relevant delay in time to disease progression or death warrants further investigation. A more pronounced effect was observed in patients with SLB-proven IPF. In conclusion, the results of the BUILD-1 study are sufficiently encouraging to be evaluated further in a larger trial. Selection of a primary endpoint of accepted clinical relevance is of paramount importance in any new trial and has already been addressed in the design of the ongoing, larger BUILD-3 morbidity/mortality study in patients with IPF.
The authors thank the investigators involved in this study: Jürgen Behr, Ishaar Bendov, Kevin Brown, Charles Chan, Jean-Francois Cordier, James Dauber, Joao de Andrade, Adaani Frost, Thomas Geiser, Marilyn Glassberg, Jeffrey Golden, Gary Hunninghake, Sanjay Kalra, Lisa Lancaster, Robert Levy, Fernando Martinez, Keith Meyer, Joachim Müller-Quernheim, Paul Noble, Christophe Pison, Charles Poirier, Ganesh Raghu, Milton Rossman, Paola Rottoli, Gerd Stähler, Dominique Valeyre, Athol Wells, Gordon Yung, David Zisman. They also thank Data Safety Monitoring Board members Ariane Herrick, David Rodman, and Jan Tijssen.
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