Table 3. Selected Bosentan Clinical Trials

Study	Patients	Bosentan Regimen	Primary	Results	Comments
Sutsch G. (1998)⁹ RDBPC	36 men NYHA-FC III	1 gram PO BID for 14 days	•Hemodynamics •Plasma neurohormones	Bosentan associated with: On Day 1: ↓ MAP, PAMP, PCWP, RAP ↓ SVR and PVR ↑ CO (HR unchanged) At 2 weeks: Further ↑ CO Further ↓ SVR and PVR After bosentan: ↑ ET-1 levels Unchanged other neurohormone levels	•Greater hemodynamic impairment in placebo group. • One patient discontinued bosentan to hypotension. •Reversible increase in hepatic transaminases.
Packer M. (1998)¹⁰ REACH-1 RDBPC	370 patients NYHA-FC IIIb-IV	500 mg PO BID for 6 months	Clinical composite (symptoms and major events)	Bosentan associated with: •Efficacy no different from placebo • ↑ likelihood of clinical improvement (B=27%, P=19%; p=0.045) • ↓ likelihood of CHF deterioration (B=27%, P=43%; p=0.045) •↓ all-cause hospitalizations by 41%	• Study terminated early due to reversible elevations in transaminases; 47% of patients were followed for 6 months (B=16.5%, P=5.2%).¹¹ • Bosentan was associated with ↓ hematocrit
Krumm H. (1999)¹¹ Open-label extension of REACH-1	86 patients from REACH-1 enrolled in open-label extension (63 B and 23 P) Less severe NYHA-FC than REACH-1	125 mg PO BID for > 6 months	Clinical composite (symptoms and major events)	•Symptom status progressively improved during the trial: NYHA-FC IIIb/IV: 21%/14% and 18%/7%, respectively. •B 125 mg PO BID was associated with fewer deaths and hospitalization than B 500 mg PO BID and P	•One patient had an increase in hepatic transaminases (previously on placebo). • Clinical improvement maintained with 125 mg PO BID and better tolerated.
Williamson D. (2000)¹² Open-label dose ranging	7 females with PAH (5 with PPH, 2 with scleroderma)	Part 1: Infusions with 50-, 150-, and 300-mg at 2 hour intervals Part 2: 1 gram PO BID for 8 weeks (randomized)	Hemodynamics	Bosentan associated with: •Dose dependent ↓ in pulmonary resistance (p=0.01) and PAMP (p>0.05). •Dose dependent ↓ SVR and MAP and ↑ in ET-1 levels.	•Part 2 terminated early when two patients in the placebo group developed hypotension and died within 36 hours of entering Part 2; rebound PHT was deemend unlikely.
Channick R. (2001)¹³ RDBPC	32 patients with severe PPH or PH	62.5 mg PO BID for 4 weeks, then 125 mg PO BID if tolerated up to 12 weeks Weeks 12 to 28 were not mandatory for all patients	Exercise capacity at week 12 (6-MWD)	•Bosentan was associated with increased 6-MWD: B=360 to 430 meters at week 12 (p<0.05) P=355 to 349 meters at week 12 6-MWD mean change: 76m (95% CI: 12 to 139; p=0.021) •PVR, PA, PCWP and MRAP were significantly ↓ with bosentan, whereas these parameters were ↑ in the placebo group.	•Functional class improved with bosentan: 43% (9/21) B patients improved to WHO class II from WHO class III at 12 weeks, and 57% (12/21) B remained class III; No patients deteriorated (p=0.0039). •Bosentan ↑ time to clinical worsening compared to placebo (p=0.033) • No hypotension or changes in hematological/ biochemical parameters. • Two bosentan patients had a transient increase in transaminases without symptoms; values returned to normal without discontinuation.
Rubin L (2002)¹ RDBPC BREATHE-1	213 patients with severe PAH (PPH 72%, rest of patients with connective tissue diseases)	62.5 mg PO BID ro 4 weeks then 125 mg PO BID or 250 mg PO BID for 12 additional weeks	Exercise capacity at week 16 (6-MWD)	•Bosentan was associated with a 44 m improvement in 6-MWD compared to placebo (95% CI: 21 to 67 m, p<0.001). •Improvement more pronounced with B 250 mg PO BID than B 125 mg PO BID (54 m, 34m). No dose response ascertained.	•B 125 mg PO BID is the clinically preferable dose. •Dose dependent liver abnormalities found with bosentan. •Aminotransferases ↑ greater than 8 times ULN: B 125 mg PO BID (n=2) B 250 mg PO BID (n=5)

RDBPC (randomized, double-blind, placebo-controlled), MAP (mean arterial pressure), MRAP (mean right arterial pressure), PCWP (pulmonary capillary wedge pressure), PAMP (pulmonary artery mean pressure), RAP (right arterial pressure), SVR (systemic vascular resistance), PVR (peripheral vascular resistance), CO (cardiac output), HR (heart rate), CHF (congestive heart failure), NYHA-FC (New York Heart Association Functional Class), 6-MWD (6-minute walk distance), ULN (upper limit normal), B (bosentan), P (placebo).

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