EARLY^† study

Tracleer improves hemodynamics, improves or maintains functional class status, and reduces rate of clinical worsening¹

Design	Dosing and duration
Randomized, double-blind, placebo-controlled trial in adult patients with PAH* WHO functional class II (N=185)	Tracleer 62.5 mg BID first 4 weeks   Tracleer 125 mg BID following 20 weeks
Primary endpoints	Exploratory endpoints*
PVR at 6 months   Change in 6MWD from baseline to month 6	Clinical worsening   Change in WHO functional class   Other hemodynamic parameters *No formal hypothesis testing was planned for these exploratory comparisons.
PAH*etiology (Tracleer treatment group)	Background therapies
IPAH: 54 (58%)   Other CTD: 9 (10%)   CHD: 16 (17%)   HIV: 5 (5%)   SSc: 9 (10%)     Baseline functional class status   100% FC II	Anticoagulants   Calcium channel blockers   Upon FDA approval, both the Tracleer group and the placebo group included some patients who were receiving sildenafil concomitantly at baseline (Tracleer, n=14; placebo, n=15).
Results
Trend toward improvement in walk distance —  19-m mean placebo-corrected 6MWD increase in Tracleer group (not significant, p=0.08)1,2   In the EARLY study, patients taking Tracleer had a baseline 6MWD of 438 m and patients taking placebo had a baseline 6MWD of 431 m.
Significantly improved hemodynamics1,2‡	80% relative risk reduction in clinical worsening at month 61-3
–197 dyn•sec/cm5 (2.46 Wood units) treatment effect. Comparable treatment effect also observed in subgroup of patients receiving sildenafil at baseline (n=28).1,3 Significantly improved CI1,2   0.24 L/min/m2 treatment effect; p<0.05 Significantly improved mPAP1,2   –5.7 mm Hg treatment effect; p<0.05)	Clinical worsening defined as:   Death   Hospitalization due to PAH*   Symptomatic progression of PAH*§ At week 243   7.6% absolute risk reduction Number needed to treat (NNT) = 13 (NNT = 1 ÷ absolute risk reduction)
97% of Tracleer patients maintained or improved functional class status by month 61-3

^†EARLY Endothelin Antagonist tRial in miLdlY symptomatic PAH* patients.

^‡The relationship between hemodynamic effects and 6MWD is unknown.

^§Symptomatic progression of PAH* was defined as the presence of 1 of the following: appearance or worsening of right heart failure (as assessed by the investigator), decrease ≥10% from baseline in two 6-minute walk tests performed ≥2 weeks apart, or ≥5% decrease from baseline in two 6-minute walk tests performed ≥2 weeks apart associated with ≥2-point increase in Borg dyspnea index.

*INDICATION
Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and to decrease clinical worsening. Studies establishing effectiveness included predominantly patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH (60%), PAH associated with connective tissue diseases (21%), and PAH associated with congenital systemic-to-pulmonary shunts (18%).

Considerations for use
Patients with WHO class II symptoms showed reduction in the rate of clinical deterioration and a trend for improvement in walk distance. Physicians should consider whether these benefits are sufficient to offset the risk of liver injury in WHO class II patients, which may preclude future use as their disease progresses.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS
Tracleer is contraindicated with cyclosporine A, glyburide, in females who are or may become pregnant, or in patients who are hypersensitive to bosentan or any component of Tracleer.

WARNINGS AND PRECAUTIONS
In clinical trials, Tracleer caused ALT/AST elevations (>3 × ULN) in 11% of patients accompanied by elevated bilirubin in a few cases. The combination of hepatocellular injury (increases in aminotransferases of >3 × ULN) and increases in total bilirubin (≥3 × ULN) is a marker for potential serious liver injury. Liver aminotransferase levels must be measured prior to initiation of treatment and then monthly. Avoid using Tracleer in patients with moderate or severe liver impairment or elevated ALT/AST >3 × ULN. If clinically significant fluid retention develops, with or without associated weight gain, the cause, such as Tracleer or underlying heart failure, must be determined. Patients may require treatment or Tracleer therapy may need to be discontinued. Preclinical data and an open-label safety study (N=25) showed a decline in sperm count of ≥50% in 25% of Tracleer-treated patients after 3 or 6 months. After 6 months, sperm count remained in normal range, with no changes in sperm morphology or motility, or hormone levels. Endothelin receptor antagonists such as Tracleer may adversely affect spermatogenesis. Treatment with Tracleer can cause a dose-related decrease in hemoglobin (Hgb) and hematocrit. Hgb should be checked after 1 and 3 months, and then every 3 months. Upon marked decrease in Hgb, determine the cause and need for specific treatment. If signs of pulmonary edema occur, the possibility of associated pulmonary veno-occlusive disease should be considered. Tracleer should be discontinued.

ADVERSE EVENTS
In Tracleer pivotal trials, the most common adverse events occurring more often in Tracleer-treated patients than in patients taking placebo (≥2%) were respiratory tract infection, edema, hypotension, sinusitis, arthralgia, liver function test abnormal, palpitations, and anemia.

Please see full Prescribing Information, including BOXED WARNING about liver injury and pregnancy.

Review Study 351 results

1. Galiè N, Rubin LJ, Hoeper MM, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008;371:2093-2100.
2. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. February 2011.
3. Data on file, Actelion Pharmaceuticals.