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	Secondary endpoints
PVR at 6 months   Change in 6MWD from baseline to month 6	Clinical worsening   Change in WHO functional class   Other hemodynamic parameters
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   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 hemodynamics1,4†	77% relative risk reduction in clinical worsening at month 61,4,5
–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). Significantly improved CI1,4   0.24 L/min/m2 treatment effect; p<0.05 Significantly improved mPAP1,4   –5.7 mm Hg treatment effect; p<0.05)	Clinical worsening defined as:   Death   Hospitalization due to PAH   Symptomatic progression of PAH†† At week 24   7.6% absolute risk reduction5 Number needed to treat (NNT) = 13 (NNT = 1 ÷ absolute risk reduction)
97% of Tracleer patients maintained or improved functional class status by month 61,4,5

*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.

Tracleer is indicated for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) in patients with WHO Class II-IV symptoms, to improve exercise ability and decrease the rate of clinical worsening. 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 potential benefits are sufficient to offset liver injury in WHO Class II patients, which may preclude future use as their disease progresses.

Important safety information

Because of the associated risks, Tracleer may be prescribed only through the Tracleer Access Program.

Potential for serious liver injury (including, after prolonged treatment, rare cases of liver failure and unexplained hepatic cirrhosis in a setting of close monitoring)—Liver monitoring of all patients is essential prior to initiation of treatment and monthly thereafter.

High potential for major birth defects—Pregnancy must be excluded and prevented through the use of reliable forms of birth control; monthly pregnancy tests should be obtained.

Contraindicated for use with cyclosporine A and glyburide.

Please see full prescribing information including BOXED WARNING.

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. Channick RN, Simonneau G, Sitbon O, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001;358:1119-1123.
3. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002;346:896-903.
4. Tracleer (bosentan) full prescribing information. Actelion Pharmaceuticals US, Inc. August 2009.
5. Data on file, Actelion Pharmaceuticals.