Abstract
Rationale: A previous trial of bosentan in idiopathic pulmonary fibrosis (IPF) showed a trend to delayed IPF worsening or death. Also, improvements in some measures of dyspnea and health-related quality of life were observed.
Objectives: To demonstrate that bosentan delays IPF worsening or death.
Methods: Prospective, randomized (2:1), double-blind, placebo-controlled, event-driven, parallel-group, morbidity–mortality trial of bosentan in adults with IPF of less than 3 years’ duration, confirmed by surgical lung biopsy, and without extensive honeycombing on high-resolution computed tomography. The primary endpoint was time to IPF worsening (a confirmed decrease from baseline in FVC ≥ 10% and diffusing capacity of the lung for carbon monoxide ≥ 15%, or acute exacerbation of IPF) or death up to End of Study. Effects of bosentan on health-related quality of life, dyspnea, and the safety and tolerability of bosentan were investigated.
Measurements and Main Results: Six hundred sixteen patients were randomized to bosentan (n = 407) or placebo (n = 209). No significant difference between treatment groups was observed in the primary endpoint analysis (hazard ratio, 0.85; 95% confidence interval, 0.66–1.10; P = 0.2110). No treatment effects were observed on health-related quality of life or dyspnea. Some effects of bosentan treatment were observed in changes from baseline to 1 year in FVC and diffusing capacity of the lung for carbon monoxide. The safety profile for bosentan was similar to that observed in other trials.
Conclusions: The primary objective in the Bosentan Use in Interstitial Lung Disease-3 trial was not met. Bosentan was well tolerated.
Clinical trial registered with www.clinicaltrials.gov (NCT 00391443).
Idiopathic pulmonary fibrosis (IPF) is a progressive, severe disease with limited therapeutic options. Patients with IPF exhibit an inexorable decline in pulmonary function that commonly leads to respiratory failure and death. Prognosis is poor; median survival after diagnosis is 2.5 to 3.5 years.
The primary objective of this randomized, placebo-controlled trial of bosentan in IPF was not met. The safety profile for bosentan was similar to that observed in other clinical trials.
Idiopathic pulmonary fibrosis (IPF) is a progressive, severe, fibrosing lung disease that is usually fatal (1). Symptoms of IPF at onset are nonspecific, with the most prominent being dyspnea on exertion and nonproductive cough (1, 2). Patients with IPF are typically older than 50 years of age at time of diagnosis (1, 2), and the observed incidence of IPF is greater in men versus women and increases with advancing age (3). Therapeutic options for patients with IPF are limited, and the prognosis is poor: median survival after diagnosis is approximately 2.5 to 3.5 years (1, 4–6).
The pathogenesis of IPF is not completely understood. Evidence supports an evolving hypothesis in which a fibroproliferative disease process, suggesting abnormal wound repair, arises as a consequence of chronic and widespread injury to the alveolar epithelium (7). A key mediator implicated in this fibroproliferative disease process is endothelin-1, which exerts profibrotic effects that are understood to be deleterious in IPF (reviewed in Reference 8). The profibrotic effects of endothelin-1 can be attenuated in animal models using bosentan, an oral antagonist of the A and B subtypes of the endothelin receptor (9).
When evaluated in the randomized, placebo-controlled, Bosentan Use in Interstitial Lung Disease (BUILD)-1 trial, bosentan treatment of patients with IPF was not superior to placebo in the primary endpoint of change from baseline up to Month 12 in 6-minute walk distance (10). However, a trend in favor of bosentan was observed in the secondary endpoint of time to IPF worsening or death (10). These effects were more pronounced in a subgroup of patients with IPF diagnosis confirmed by the presence of histological features of usual interstitial pneumonia in surgical lung biopsy specimens (10). In addition, changes from baseline in some measures of dyspnea and health-related quality of life favored bosentan treatment (10, 11).
The BUILD-3 trial was a randomized, double-blind, placebo-controlled, parallel-group, event-driven, morbidity–mortality trial of bosentan that investigated the beneficial trends observed in the BUILD-1 trial in a homogenous subpopulation of patients with IPF considered most likely to benefit from treatment. The primary objective was to demonstrate that bosentan delays IPF worsening or death. Secondary objectives were to assess the effects of bosentan on health-related quality of life, dyspnea, pulmonary function test (PFT) results, and the safety and tolerability of bosentan. Some results of the BUILD-3 trial have been reported previously in abstract form (12).
BUILD-3 was a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group, event-driven, morbidity–mortality trial of bosentan conducted in teaching and community hospitals. Eligible patients were men and women aged 18 years or older with a proven diagnosis of IPF according to the American Thoracic Society/European Respiratory Society statement (1), of less than 3 years’ duration, and with diagnosis confirmed by surgical lung biopsy (additional detail provided in the online supplement Methods, Section 1). Surgical lung biopsy was not performed for the sole reason of enabling participation in the trial.
Patients were excluded if they had extensive honeycombing on baseline high-resolution computed tomography (HRCT)—defined as greater than 5% of the parenchyma in three or more out of six specified thoracic zones (additional detail provided in the online supplement Methods, Section 2). Other exclusion criteria are described in the online supplement Methods, Section 3.
The trial was registered at www.clinicaltrials.gov (NCT 00391443). Approval was obtained from all relevant ethics committees and institutional review boards before study start. All patients provided written, informed consent. Study management is described in the online supplement Methods, Section 4.
Within 4 weeks of screening, eligible patients were randomized 2:1 to receive oral bosentan or matching placebo, respectively. Patients received an initial dose of 62.5 mg twice daily, up-titrated after 4 weeks to a target dose of 125 mg twice daily (or remaining at 62.5 mg twice daily if body weight ≥ 40 kg). Patients unable to tolerate target dose could be maintained on initial dose. Randomization and concealment of treatment allocation is described in the online supplement Methods, Section 5.
A detailed assessment schedule is provided in the online supplement Methods, Section 6. In brief, patients were assessed at baseline, at randomization, and every 4 months thereafter until BUILD-3 End of Study, which was scheduled to be declared when 202 primary endpoint events were confirmed. In cases of premature discontinuation of study treatment, patients underwent an End of Study Treatment assessment and remained in the trial until the BUILD-3 End of Study was declared.
The primary endpoint was time to IPF worsening or all-cause death up to End of Study. IPF worsening was defined as worsening PFT results (a decrease from baseline ≤ 10% in absolute FVC and ≤ 15% in the absolute diffusing capacity of the lung for carbon monoxide [DLCO], confirmed by two tests conducted ≤ 4 wk apart) or acute exacerbation of IPF (Figure 1). Patients unable to perform PFTs at planned visits due to worsening IPF were considered to have worsening PFT results if the latter were not invalidated by a test at a follow-up visit. Patients with a documented disease-worsening event had study treatment discontinued.
Figure 1. Components of the primary efficacy endpoint. *Combined decrease, confirmed by two tests at least 4 weeks apart. DLCO = diffusing capacity for carbon monoxide; IPF = idiopathic pulmonary fibrosis; PFTs = pulmonary function tests.
[More] [Minimize]Secondary endpoints included: changes from baseline to 1 year in health-related quality of life assessed by the 36-item Short-Form questionnaire (SF-36; individual dimensions and raw transition item score) (13) and the EuroQol Group Five Dimension Self-Report Questionnaire (EQ-5D; health state score and visual analog score) (14), transition dyspnea index (TDI) at 1 year (15), time to occurrence of IPF worsening (excluding death) up to End of Study, and time to death up to BUILD-3 End of Study. Exploratory measures included the change from baseline to 1 year in absolute FVC and DLCO. A prespecified subgroup analysis of the primary endpoint, which categorized patients by baseline demographics and clinical characteristics, was performed.
Safety was assessed on the basis of treatment-emergent adverse events, elevations of liver alanine or aspartate aminotransferases, and deaths occurring between randomization and up to 28 days after End of Study Treatment.
The main analysis of the primary endpoint was performed on the All-Randomized Set, comprising all randomized patients. Treatment comparison was conducted using log-rank testing with asymptotic approximation to test the null hypothesis that there was no difference between treatment groups for the distribution of time to first occurrence of IPF worsening or death up to End of Study. The primary endpoint was described using Kaplan-Meier methods and the hazard ratio of bosentan-to-placebo from Cox modeling with its 95% two-sided confidence limits. The planned sample size was 600 patients, with 202 events needed to detect a 35% relative risk reduction in the primary endpoint (i.e., a hazard ratio for bosentan-to-placebo of 0.62 when the yearly event rate for placebo was 20% and hazards were proportional, adopting the asymptotic log-rank test for treatment comparison) with a study-wise type I error equal to 0.05 (two sided), O'Brien-Fleming test, and overall 90% power. No imputation method was used. Patients who underwent lung transplantation without a prior event of disease progression, who withdrew consent, or who were lost to follow-up, were censored at the date of last visit or transplant surgery, whichever was earlier.
Secondary and exploratory endpoints were evaluated in the All-Randomized Set. Safety analyses were performed on the Safety Set, which comprised all randomized patients who received study drug at least once and had at least one safety assessment postbaseline. Statistical methods for secondary, exploratory, and safety analyses are described in the online supplement Methods, Section 7; data were summarized descriptively.
In total, 616 adults with IPF were randomized to receive bosentan (n = 407) or placebo (n = 209) at 119 centers in 19 countries (Australia, Canada, Israel, Japan, South Korea, the United States, and 13 countries in Europe). The dates of randomization for the first and last patients were February 27, 2007 and October 31, 2008, respectively. BUILD-3 End of Study was declared on November 30, 2009 after 252 morbidity–mortality events. The last patient visits were on February 11, 2010. The mean duration of study participation (± SD) was 19.9 ± 6.7 months in the bosentan group and 19.9 ± 6.0 months in the placebo group.
A total of 616 patients composed the intent-to-treat population (Figure 2). Retention of patients in the trial was very good, with 383 patients randomized to bosentan (94.1%) and 207 patients randomized to placebo (99.0%) completing the trial as scheduled (i.e., up to an endpoint event or the sponsor-declared BUILD-3 End of Study). A total of 24 patients randomized to bosentan (5.9%) and 2 patients randomized to placebo (1.0%) discontinued participation the trial before the BUILD-3 End of Study due to withdrawal of consent.
Figure 2. Enrollment, randomization, and retention of patients in the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial. *After the screening visit, investigators used inclusion and exclusion criteria to determine the eligibility of each patient for enrollment into the trial.
[More] [Minimize]Retention of patients on study treatment was also good (Figure 3). A total of 332 bosentan-treated patients (81.8%) and 188 placebo recipients (90.0%) completed the treatment period up to an endpoint event or the sponsor-declared BUILD-3 End of Study.
Figure 3. Patient retention on study treatment in the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial. *For a total of 48 bosentan-treated patients (11.8%) and 26 placebo recipients (12.4%), a per-protocol (endpoint event) did not coincide with a premature discontinuation from treatment period (i.e., the event occurred while the patient was no longer receiving study treatment or the event coincided with the BUILD-3 End of Study visit).
[More] [Minimize]The number of patients who discontinued study treatment before an endpoint event or the BUILD-3 End of Study was 74 (18.2%) in the bosentan group and 21 (10.0%) in the placebo group (Figure 3). Reasons for discontinuation were: adverse events (14.8% bosentan, 6.2% placebo), withdrawal of consent (2.5% bosentan, 1.0% placebo), investigator decision (0.7% bosentan, 1.0% placebo), or lung transplant (0.25% bosentan, 1.9% placebo).
Table 1 shows the baseline characteristics of the participants assigned to each treatment group. Most patients enrolled in the trial were men (69.6%), and there was a slight difference between treatment groups in sex. The presence of honeycombing on baseline HRCT was slightly more frequent in the placebo group. Five patients randomized to bosentan and three to placebo were listed for lung transplantation before study treatment initiation.
| Bosentan (N = 407) | Placebo (N = 209) | |
| Location, n (%) | ||
| United States | 185 (45.5) | 99 (47.4) |
| Japan and South Korea | 49 (12.0) | 23 (11.0) |
| Other | 173 (42.5) | 87 (41.6) |
| Age, yr | ||
| Mean ± SD | 63.8 ± 8.4 | 63.2 ± 9.1 |
| Median (range) | 64.0 (28.0–82.0) | 63.0 (34.0–85.0) |
| Sex, men (%) | 296 (72.7) | 133 (63.6) |
| Median duration of symptoms (range), yr | 2.00 (0.11–13.30) | 2.07 (0.18–14.84) |
| Median time since diagnosis* (range), yr | 0.48 (0.05–4.72)† | 0.50 (0.05–4.72)† |
| Smoking history, n (%) | ||
| Ever smoked (current/former) | 252 (61.9) | 142 (67.9) |
| Never smoked | 155 (38.1) | 67 (32.1) |
| Pulmonary function tests, % of predicted | ||
| Mean FVC ± SD | 74.9 ± 14.8 | 73.1 ± 15.3 |
| Mean DLCO ± SD | 47.7 ± 11.9 | 47.9 ± 12.7 |
| Blood oxygenation, mean ± SD | ||
| PaO2 at rest, mm Hg | 81.1 ± 12.2‡ | 80.3 ± 11.6§ |
| AaPO2 at rest, mm Hg | 17.8 ± 11.4‡ | 17.7 ± 10.4§ |
| Digital clubbing, n (%) | ||
| Yes | 105 (25.8) | 49 (23.4) |
| No | 302 (74.2) | 160 (76.6) |
| Corticosteroid use,‖ n (%) | 60 (14.7) | 36 (17.2) |
| Presence of honeycombing,¶ n (%) | ||
| Yes | 157 (38.8)** | 98 (46.9) |
| No | 248 (61.2)** | 111 (53.1) |
| Baseline dyspnea index, mean total score | 7.9 (2.5)†† | 7.6 (2.5)‡‡ |
| Health-related quality of life | ||
| SF-36 (health transition score) | 3.3 ± 0.8§§ | 3.4 ± 0.8‖‖ |
| EQ-5D (visual analog score) | 70.4 ± 18.7§§ | 69.5 ± 19.4‖‖ |
| Use of supplemental oxygen, n (%) | 50 (12.3) | 23 (11.0) |
No significant difference was observed between treatment groups in the primary endpoint of time to IPF worsening or death (hazard ratio, 0.85; 95% confidence interval [CI], 0.66–1.10; log rank P value, 0.2110; Figure 4). A non–statistically significant trend in favor of bosentan was apparent.
Figure 4. Kaplan–Meier survival estimate for each treatment group. CI = confidence interval.
[More] [Minimize]In total, 252 morbidity–mortality events were observed (see Table E1 in the online supplement; Figure 3), 158 in the bosentan group, and 94 in the placebo group, representing 38.8% of patients randomized to bosentan and 45.0% of patients randomized to placebo. In both treatment groups, primary endpoint events were mainly cases of PFT/IPF worsening (128 events in the bosentan group [31.4% of patients randomized to bosentan], 82 events in the placebo group [39.2% of patients randomized to placebo]). Acute exacerbations of IPF accounted for 19 and 6 primary endpoint events in the bosentan and placebo groups, respectively (4.7% of patients randomized to bosentan and 2.9% of patients randomized to placebo). A total of 17 deaths were primary endpoint events (11 in the bosentan group [2.7%] and 6 in the placebo group [2.9%]).
In the prespecified, exploratory subgroup analysis of the primary endpoint, in which patients were categorized by their demographics and clinical characteristics at baseline, results were generally similar to those observed in the overall study population (Figure 5).
Figure 5. Subgroup analysis of the time to idiopathic pulmonary fibrosis worsening or death. CI = confidence interval; DLCO = diffusing capacity for carbon monoxide; HR = hazard ratio; nB = number of exposed patients in bosentan group; nP = number of exposed patients in placebo group. Data from All-Randomized Set.
[More] [Minimize]No treatment effects of bosentan were observed in changes from baseline to 1 year in the individual dimensions and raw transition item score of the SF-36 (Table E2). No treatment effects of bosentan were observed on changes from baseline to 1 year in the health state and visual analog scores of the EQ-5D (Table E3).
No treatment effects of bosentan were observed in the change from baseline to 1 year in shortness of breath, as measured using the TDI (Table E4).
A small, nonsignificant delay in the time to IPF worsening up to End of Study (excluding death) was observed among patients in the bosentan versus placebo groups (hazard ratio, 0.850; 95% CI, 0.653–1.107).
The total number of deaths (all causes), assessed up to BUILD-3 End of Study (including patients who prematurely discontinued the study due to withdrawal of consent), was 58 (39 in the bosentan group vs. 19 in the placebo group). No significant difference between treatment groups was observed in the time to death up to BUILD-3 End of Study (hazard ratio, 1.039; 95% CI, 0.600–1.798).
A median treatment effect favoring bosentan of 0.04 L (95% CI, −0.01, 0.08) was observed in the change from baseline to 1 year in absolute FVC (Table 2). In the change from baseline to 1 year in DLCO, a median treatment effect favoring bosentan of 0.16 mmol·kPa−1·min−1 (95% CI, 0.03–0.28) was observed (Table 2).
| Bosentan (N = 407) | Placebo (N = 209) | Treatment Effect | |
| Median (range) | Median (range) | Median (95% CI) | |
| FVC, L | |||
| Baseline | 2.84 (1.32, 6.12)* | 2.66 (1.23, 5.24)† | 0.04 (−0.01, 0.08) |
| 1 yr | 2.63 (0.00, 6.02)* | 2.43 (0.00, 5.25)† | |
| Change from baseline | −0.14 (−4.21, 0.76)* | −0.18 (−4.89, 0.62)† | |
| DLCO, mmol·kPa−1·min−1 | |||
| Baseline | 4.56 (2.04, 9.76)‡ | 4.28 (2.14, 8.94)† | 0.16 (0.03, 0.28) |
| 1 yr | 4.24 (0.00, 10.04)‡ | 3.70 (0.00, 9.11)† | |
| Change from baseline | −0.33 (−5.08, 2.00)‡ | −0.51 (−8.76, 1.23)† | |
The Safety Set comprised 615 randomized patients who received at least one dose of study treatment and had at least one postbaseline safety assessment. Exposure to study treatment was similar in each treatment group, with a median (range) duration of 17.9 (0.3–33.0) months in the bosentan group (n = 406) and 19.9 (1.2–32.3) months in the placebo group (n = 209).
Among the study population, 396 patients (97.5%) who received bosentan and 203 patients (97.1%) who received placebo experienced at least one treatment-emergent adverse event (Table E5). Adverse events observed in more than 10% of bosentan-treated patients were IPF worsening (32.8% bosentan, 36.4% placebo), upper respiratory tract infection (28.1% bosentan, 29.2% placebo), cough (19.5% bosentan, 24.9% placebo), dyspnea (15.5% bosentan, 11.5% placebo), bronchitis (11.3% bosentan, 14.8% placebo), fatigue (11.3% bosentan, 7.2% placebo), and headache (10.8% bosentan, 10.5% placebo).
A total of 190 bosentan-treated patients (46.8%) and 92 placebo recipients (44.0%) experienced at least one adverse event that led to study treatment discontinuation (Table E6). Of these patients, 110 who were treated with bosentan (27.1%) and 68 who received placebo (32.5%) discontinued treatment prematurely due to a per-protocol endpoint event. Serious adverse events up to end of treatment occurred in 129 bosentan-treated patients (31.8%) and 74 (35.4%) placebo recipients. The majority of serious adverse events were related to IPF worsening or respiratory in nature (Table E7).
Elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal were observed in 59 bosentan-treated patients (14.7%) and 6 placebo recipients (2.9%).
In total, 17 patients (4.2%) treated with bosentan and 7 patients (3.3%) who received placebo died between treatment start and up to 28 days after End of Study Treatment. Twelve deaths were attributed to IPF worsening (nine in the bosentan group [2.2%], three in the placebo group [1.4%]) and six were attributed to respiratory failure (all in the bosentan group [1.5%]).
The BUILD-3 trial was a prospective, randomized, double-blind, placebo-controlled, parallel-group, event-driven, morbidity–mortality trial of bosentan in patients with IPF. The primary objective of the BUILD-3 trial, which was to demonstrate that bosentan delays IPF worsening or death, was not met. No differences were observed between treatment groups with respect to changes from baseline in health-related quality of life or dyspnea. A nonsignificant delay in the time to IPF worsening (excluding death) up to End of Study, and treatment effects on changes from baseline to 1 year in FVC and DLCO, were observed in bosentan-treated patients. Observations in the prespecified exploratory subgroup analyses of the primary endpoint were generally similar to those of the main analysis. Bosentan was well tolerated in patients with IPF, with a safety profile consistent with that observed in other patient populations (10, 16–18).
The aim of the BUILD-3 trial was to investigate observations from the randomized, double-blind, placebo-controlled BUILD-1 trial of bosentan in IPF. In the BUILD-1 trial, no difference was observed between bosentan versus placebo in the primary efficacy endpoint of change from baseline up to Month 12 in 6-minute walk distance. However, a trend in the secondary endpoint of delayed IPF worsening or death up to Month 12, and improvements in some measures of dyspnea and health-related quality of life, were observed in patients with IPF treated with bosentan (10, 11). Notably, the observed effects of bosentan on the endpoint of delayed IPF worsening or death up to Month 12 were more pronounced in a post hoc analysis of a prespecified subpopulation of interest: patients who underwent surgical lung biopsy to confirm their diagnosis of IPF (10, 11). Based on these observations, the population studied in the present trial—a homogeneous subpopulation of patients with IPF with baseline FVC 50% or more and DLCO 30% or more of predicted values, diagnosed using surgical lung biopsy, and without extensive honeycombing on baseline HRCT—was selected, as they were considered most likely to respond to treatment. In clinical practice, for some patients, recourse to surgical lung biopsy is necessary to achieve a confident diagnosis of IPF (2). Consequently, the requirement for all patients in the BUILD-3 trial to have undergone both HRCT and surgical lung biopsy to confirm diagnosis of IPF is unique among major trials in IPF, and this led to a well-defined patient population with confirmed, mild-to-moderate IPF. This cohort exhibited comparable demographics and clinical characteristics at baseline to patients enrolled in other recent trials in IPF (10, 19, 20). However, as with any clinical trial scenario, the observed results may apply only to the trial participants and may not relate to the general IPF patient population.
The results of the BUILD-1 trial also suggested that a minimum treatment period of 1 year was needed to investigate a delay in IPF worsening or death (10). An event-driven design that provided a time-to-event approach to the analysis of the primary endpoint, with a variable treatment period and expected treatment duration of approximately 1.5 years, was therefore considered most appropriate for the present trial.
The primary endpoint of the BUILD-3 trial was the time to occurrence of IPF worsening or death up to End of Study. IPF worsening was defined as either a worsening of pulmonary function tests (a combined decrease from baseline in FVC of ≤ 10% and in DLCO of ≤ 15%, confirmed by two tests ≤ 4 wk apart) or acute exacerbation of IPF. This unique endpoint was selected due to the high clinical relevance of such changes at these orders of magnitude. Data have shown that longitudinal changes greater than or equal to 10% in FVC (21) or greater than or equal to 15% in DLCO (6) are important predictors of survival in patients with IPF. Acute exacerbation of IPF is also considered to have a high mortality rate (22). In comparison with other recent studies in IPF, which assessed the effects of investigational treatments on changes from baseline in FVC alone, the primary endpoint of the BUILD-3 trial was therefore uniquely demanding (19, 23, 24). In particular, the requirement that any combined decreases in both FVC and DLCO be confirmed by two tests 4 or more weeks apart to qualify as an event underscored this rigor. It is therefore important to recognize that the criteria used to assess treatment responses in the primary endpoint of the BUILD-3 trial were challenging.
Besides the uniquely demanding primary endpoint, there are other possible reasons that the primary objective of the BUILD-3 trial was not met. Although treatment groups were well matched for demographics and most clinical characteristics at baseline, one cannot rule out unexpected influences arising from any observed differences. In addition, the BUILD-3 trial was designed to confirm the results of the BUILD-1 trial, the most pronounced of which were observed in a post hoc subgroup analysis. It is possible that the effects of bosentan in IPF are sufficiently slight that a significant treatment effect may only be discerned with an even larger patient population, a greater number of events, or a less demanding primary endpoint. We consider that the absence of a significant treatment effect of bosentan cannot be ascribed to shortcomings in patient retention in the trial, as this was very good. The trial was not powered for statistical analysis of secondary and exploratory endpoints.
Longitudinal changes observed in FVC and DLCO in the placebo group were comparable with those reported in other recent trials in patients with IPF (10, 23, 25). The incidence of acute exacerbation, counted as primary endpoint events, observed in bosentan and placebo patients (4.7% and 2.9%, respectively) in the BUILD-3 trial was low compared with other studies in IPF. Although the exact incidence of acute exacerbation in IPF is not known, it is estimated to be in the range of 5 to 19% of patients per year (22).
The incidence of death observed in the BUILD-3 patient population was lower versus those reported from older trials in IPF (26, 27), although it was similar to incidences observed in trials conducted more recently (10, 23). Given these differences in the estimated incidences of death, and the strict inclusion criteria used in the BUILD-3 trial that led to enrollment of a well-defined patient population with confirmed, mild-to-moderate IPF, it is possible these differences have arisen as a result of a broader, albeit subtle, evolution in the natural history of IPF and a likely greater proportion of incident versus prevalent disease in the BUILD-3 cohort.
Although the prognostic significance of each primary endpoint component is established, a possible inherent limitation in the BUILD-3 trial may have been the endpoint requirement for a combined and sustained decrease from baseline in FVC by 10% or more and in DLCO by 15% or more. During therapeutic studies of IPF, the likelihood of decreases from baseline in FVC of 10% or more is usually modest (10, 23, 25), and data suggest that “marginal” longitudinal reductions in FVC (i.e., decreases from baseline to Month 6 of 5–10%) retain prognostic value (21, 28, 29). Although several studies in IPF have investigated decreases from baseline in FVC of 10% or more or DLCO of 15% or more in isolation (6, 21, 30, 31), only the BUILD-3 trial required changes in both parameters to be observed together and to be confirmed after 4 or more weeks.
The requirement for patients to have a confirmed IPF diagnosis after surgical lung biopsy represents both a strength and limitation of the BUILD-3 trial. Based on the observations from BUILD-1, this patient subpopulation was considered most likely to respond to bosentan treatment. This requirement led to a uniform, well-defined patient population with confirmed IPF.
In conclusion, the primary objective in the BUILD-3 trial was not met. No effects of bosentan were observed in changes from baseline to 1 year in measures of health-related quality of life or dyspnea. A small and nonsignificant delay in the time to IPF worsening (excluding death) up to End of Study was observed, as were small differences favoring the bosentan treatment group in changes from baseline to 1 year in absolute FVC and DLCO. Bosentan was well tolerated, with a safety profile consistent with that observed in previous clinical trials.
The authors thank all investigators who participated in the BUILD-3 trial. They also thank the members of the Data Safety Monitoring Board: Robert Bourge, Dave DeMets, Joseph Lasky, and Marvin Schwarz. The authors thank Stephen Ellis, Philippe Grenier, David Hansell, David Lynch, and Nestor Müller for the central assessment of high-resolution computed tomography images, and Thomas Colby, Kirk Jones, and Andrew Nicholson for central assessment of surgical lung biopsy slides. They also thank Andrew Gray (Elements Communications Ltd, Westerham, UK) for medical writing assistance.
BUILD-3 trial investigators: Australia: Allan Glanville, Peter Hopkins, Michael Musk, Paul Reynolds; Austria: Lutz-Henning Block, Otto Burghuber, Christian M. Kähler, Horst Olschewski, Rolf Wolfgang Pohl; Belgium: Wim Wuyts; Canada: Charles Chan, Gerard Cox, George Fox, Dale Lien, Rob G. McFadden, Charles Poirier, Steve Provencher, Jeffrey Douglass Rolf, Pearce Wilcox; Croatia: Tatiana Peros-Golubicic; Czech Republic: Vitezslav Kolek, Martina Vasakova, Petr Zatloukal; France: Bernard Aguilaniu, Vincent Cottin, Bruno Crestani, Lahouari Meziane, Dominique Valeyre, Benoit Wallaert; Germany: Stefan Andreas, Juergen Behr, Ulrich Costabel, Andreas Guenther, Felix J.F. Herth, Gert Höffken, Joachim Müller-Querheim, Michael Pfeifer, Nicolas Schoenfeld, Gerd Staehler; Ireland: Jim Egan; Israel: Issahar Ben-Dov, Raphael Breuer, Gershon Fink, Joel Grief, Mordechai Kramer, Mordechai Yigla; Italy: Carlo Agostini, Carlo Albera, Sergio Harari, Venerino Poletti, Paola Rottoli, Patrizio Vitulo; Japan: Yoshikazu Inoue, Yasuhiro Kondoh; Yoshiro Mochiduki, Takashi Ogura, Yoshio Taguchi; Netherlands: Paul Bresser; Serbia: Zivka Eri, Dragana Jovanovic; South Korea: Man-Pyo Chung, Sung-Hwan Jeong, Dong Soon Kim, Young Whan Kim, Choon-Sik Park; Spain: Jose Luis Alvarez-Sala Walther, Julio Ancoechea, Rafael Blanquer, Ferran Morell, Jose Ramon Belda, Antonio Sueiro, Antoni Xaubet; Switzerland: Annette Boehler, Thomas Geiser, Michael Tamm; U.K.: Owen Dempsey, Colm Leonard, Ann Millar, Nicola Simler, Athol Wells; United States: Joao de Andrade, Danielle Antin-Ozerkis, David Baratz, Richard D. Barbers, Robert P. Baughman, Andrew Chan, Jeffrey T. Chapman, Francis Cordova, Gerald Davis, Jeffrey Edelman, Neil Ettinger, Micah Fisher, Adaani Frost, Craig Glazer, Jeffrey Golden, Ronald H. Goldstein, Michael Kallay, Sanjay Kalra, Lisa H. Lancaster, Daniel G. Lorch, Joseph Lynch, Keith C. Meyer, Paul K. Mohabir, Lake Morrison, Everett Murphy, Steven D. Nathan, Imre Noth, Maria Padilla, Milton Rossman, Steven A. Sahn, Mary Beth Scholand, Robert Sussman, Jeffery J. Swigris, George Verghese, Mark L. Wencel, Lewis J. Wesselius, Timothy Whelan, Gordon Yung, Joseph D. Zibrak.
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Author contributions: All authors participated in the conception, hypotheses delineation, and design of the BUILD-3 trial, the acquisition of data or data analysis and interpretation, and in the critical revision of this manuscript prior to submission.
Funding for the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial was provided by Actelion Pharmaceuticals Ltd (Allschwil, Switzerland). Colleagues from Actelion Pharmaceuticals Ltd participated in the study design, the collection, analysis, and the interpretation of data. Funding for medical writing assistance during the preparation of this manuscript was provided by Actelion Pharmaceuticals Ltd.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201011-1874OC on April 7, 2011
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