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Sitaxsentan Therapy for Pulmonary Arterial Hypertension

Columbia University College of Physicians & Surgeons, New York, New York; Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada; Harbor-University of California at Los Angeles Medical Center, Torrance; University of Southern California, Los Angeles, California; Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois; Rhode Island Hospital, Providence, Rhode Island; Duke University Medical Center, Durham, North Carolina; Vanderbilt University Hospital, Nashville, Tennessee; University of Wisconsin Medical Center, Milwaukee, Wisconsin; ICOS Corporation, Bothell, Washington; Baylor College of Medicine; and Encysive Pharmaceuticals, Houston, Texas

Correspondence and requests for reprints should be addressed to Robyn J. Barst, M.D., Columbia University College of Physicians & Surgeons, 3959 Broadway, BHN 2-255, New York, NY 10032-1551. E-mail: rjb3{at}columbia.edu

	ABSTRACT

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Sitaxsentan may benefit patients with pulmonary arterial hypertension by blocking the vasoconstrictor effects of endothelin-A while maintaining the vasodilator/clearance functions of endothelin-B receptors. Patients with pulmonary arterial hypertension that was idiopathic, related to connective tissue disease or congenital heart disease, were randomized to receive placebo (n = 60), sitaxsentan 100 mg (n = 55), or sitaxsentan 300 mg (n = 63) orally once daily for 12 weeks. The primary endpoint was change in peak O₂ at Week 12. Secondary endpoints included 6-minute walk, New York Heart Association class, O₂ at anaerobic threshold, E per carbon dioxide production at anaerobic threshold, hemodynamics, quality of life, and time to clinical worsening. Although the 300-mg group increased peak O₂ compared with placebo (+3.1%, p < 0.01), none of the other endpoints derived from cardiopulmonary exercise testing were met. However, both the 100-mg dose and the 300-mg dose, compared with placebo, increased 6-minute walk distance (100 mg: +35 m, p < 0.01; 300 mg: +33 m, p < 0.01); functional class, cardiac index, and pulmonary vascular resistance also improved (p < 0.02 for each parameter at both doses). The incidence of elevated aminotransferase values (> three times normal) was 3% for the placebo group, 0% for the 100-mg group, and 10% for the 300-mg group.

Key Words: endothelins • exercise • hypertension, pulmonary • pulmonary heart disease

Pulmonary arterial hypertension (PAH), characterized by vasoconstriction and structural changes in the small pulmonary muscular arteries and arterioles, is a devastating disease with progressive elevation of pulmonary artery pressure (Ppa) and pulmonary vascular resistance, ultimately producing right heart failure and death (1).

Endothelin (ET) is an endogenous peptide with potent vasoconstrictor, mitogenic, and profibrotic effects (2) and appears to play a significant role in the pathophysiology of PAH. Patients with PAH have increased plasma ET levels and increased expression of ET in the pulmonary vasculature (3, 4). In a small cohort of patients with idiopathic PAH, plasma concentrations of ET correlated with Ppa and pulmonary vascular resistance, as well as with exercise capacity (5).

Two distinct ET receptor isoforms have been identified, ET_A and ET_B (6). Activation of ET_A receptors facilitates sustained vasoconstriction and proliferation of vascular smooth muscle cells (6). In contrast, ET_B receptors are believed to be principally involved in the clearance of ET, particularly in the vascular beds of the lung and kidney (6). To date, bosentan, the oral ET_A and ET_B receptor antagonist, is the only approved ET receptor antagonist for the treatment of PAH (7, 8).

Selective antagonism of ET_A receptors may be more beneficial than antagonism of both ET_A and ET_B receptors for the treatment of PAH by blocking the vasoconstrictor effects of ET_A while maintaining the vasodilator and clearance functions of ET_B receptors (9). Sitaxsentan sodium is a potent ET receptor antagonist that has oral bioavailability and a long duration of action (t¹/₂, 5–7 hours) (10). Sitaxsentan is approximately 6,500-fold more selective as an antagonist for ET_A compared with ET_B receptors (10). The primary objectives of the Sitaxsentan To Relieve Impaired Exercise (STRIDE-1) Trial were to evaluate the safety and efficacy of sitaxsentan in patients with symptomatic PAH. Some of the results from this study have been previously reported in abstract form (11, 12).

	METHODS

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Study Population
Patients between the ages of 16 and 75 years with symptomatic PAH despite treatment with anticoagulants, vasodilators, diuretics, cardiac glycosides, or supplemental oxygen were eligible for study participation if they met the following criteria: (1) PAH that was idiopathic, related to connective tissue disease, or related to congenital systemic-to-pulmonary shunts (repaired or unrepaired); (2) peak O₂ that was between 25 and 75% of predicted; and (3) mean pulmonary artery pressure () higher than 25 mm Hg at rest, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure lower than 15 mm Hg, and pulmonary vascular resistance higher than or equal to 240 dynes/second/cm^-5. Patients were excluded if they had significant parenchymal lung disease, portal hypertension, chronic liver disease, history of human immunodeficiency virus infection, hepatic dysfunction (serum aminotransferase level > three times upper limit of normal), chronic renal insufficiency, or received any chronic prostaglandin (PG), PG analog, or ET receptor antagonist therapy within 30 days before study entry.

The study was conducted according to the ethical principles stated in the Declaration of Helsinki (1996) and applicable guidelines on Good Clinical Practice. The protocol was approved by local institutional review committees, and written informed consent was obtained from all patients.

Study Design and Randomization
The study was a randomized, double-blind, placebo-controlled trial that enrolled 178 patients between July 2001 and May 2002 at 23 centers (22 in the United States, 1 in Canada). Patients were randomized to receive placebo, sitaxsentan 100 mg, or sitaxsentan 300 mg once daily given orally for 12 weeks. Randomization was performed centrally and stratified by center in blocks according to a computer-generated random number table. All patients who completed the 12-week study were eligible to enter a blinded extension study and receive sitaxsentan 100 or 300 mg.

Outcome Measures
Patients were evaluated at Study Weeks 1 and 2 and every 2 weeks thereafter through Week 12. The primary endpoint was: percent of predicted peak O₂ (measured during cycle ergometry) (13). Secondary endpoints were: 6-minute walk distance, New York Heart Association (NYHA) functional class, O₂ at anaerobic threshold (AT), E per carbon dioxide production (E/CO₂) at AT, hemodynamic parameters (, mean right atrial pressure, cardiac index, and pulmonary vascular resistance), quality of life (as measured by the Medical Outcomes Study Short-Form 36) (14), and time to events of clinical worsening defined as death, epoprostenol use, atrial septostomy, or transplantation. Safety was assessed by adverse events and laboratory evaluations.

Peak O₂, O₂ at AT, and E/CO₂ at AT were measured during cycle ergometry conducted at baseline, Week 6, and Week 12. Right heart catheterization was performed at baseline and Week 12. For hemodynamic calculations, O₂ was measured in all patients with residual or unrepaired congenital systemic-to-pulmonary shunts. Clinical laboratories and trough plasma sitaxsentan concentrations were evaluated at baseline and every 2 weeks thereafter through Week 12, with more extensive pharmacokinetic sampling performed in a subset of patients at Days 2 (first day of dosing in this subset) and 84. Patients were discontinued from the study if they had deterioration of NYHA functional class, an elevation in total bilirubin more than two times the upper limit of normal plus a serum aminotransferase value more than three times the upper limit of normal, or a serum aminotransferase value more than five times the upper limit of normal.

Statistical Analysis
Percent of predicted peak O₂ was defined as observed peak O₂ divided by the predicted peak O₂ on the basis of normalization by weight, height, age, and sex, multiplied by 100 ([peak O₂/predicted peak O₂] x 100) (13). The efficacy analysis was prospectively defined and conducted according to the intent-to-treat principle, consisting of analysis of all patients who received any dose of study drug and according to the group randomized. All efficacy endpoints were analyzed by comparison of the placebo group with each sitaxsentan group separately. Changes in the primary efficacy endpoint were separately analyzed by a parametric analysis of covariance model (15) and a nonparametric analysis of covariance (based on ranks) (15), with baseline value as the covariate. Changes in secondary endpoints were analyzed as follows: (1) for continuous endpoints, e.g., 6-minute walk distance, the parametric analysis of covariance model described previously was used; (2) for categoric endpoints, e.g., NYHA class, a Cochran–Mantel–Haenszel procedure (16) was used; and (3) for time to event endpoints, Kaplan–Meier methodology was used. Safety data were analyzed according to actual treatment received.

Based on prespecified rules, missing values were replaced using the last observation carried forward data imputation method. If no postbaseline value was available, the baseline value was carried forward.

Interim Monitoring
An independent, external Data and Safety Monitoring Board conducted two interim safety evaluations based on adverse events and laboratory data after 45 and 90 patients completed Week 12 assessments. In addition, the Sponsor and Data and Safety Monitoring Board reviewed serious adverse events and elevated liver function enzyme values by blinded, masked treatment groups from both the current study and the extension trial on an ongoing basis. Only the Data and Safety Monitoring Board was authorized to request unblinding of safety data by treatment groups.

	RESULTS

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Patients
A total of 178 patients were enrolled: 60 received placebo and 118 received sitaxsentan (55 patients, 100 mg; 63 patients, 300 mg). Twelve patients prematurely discontinued the study. Reasons for discontinuation in the placebo group (n = 5) were three patients for worsening PAH, one for liver enzyme elevation, and one was lost to follow-up. In the 300-mg group (n = 7), three patients discontinued for worsening PAH, three for liver enzyme elevation, and one for renal insufficiency. None of the patients in the 100-mg group discontinued prematurely.

Table 1 shows the baseline characteristics of patients. The cause of PAH was idiopathic in 94 (53%) patients, related to connective tissue disease in 42 (24%), and related to congenital systemic-to-pulmonary shunts in 42 (24%) patients. Of patients with congenital shunts, 14 were repaired and 28 were unrepaired. The three treatment groups were well matched for baseline characteristics.

View this table: [in this window] [in a new window]   TABLE 2. Change from baseline in percent of predicted peak O2, O2 at anaerobic threshold, and E per carbon dioxide (E/CO2) production at anaerobic threshold in placebo and sitaxsentan groups

View larger version (16K): [in this window] [in a new window]   Figure 1. Mean (± SE) change in 6-minute walk distance from baseline to Week 12 in placebo and sitaxsentan groups. Pairwise (vs. placebo) p values are from analysis of covariance including baseline response in the model and are adjusted for multiple comparisons using Dunnett's method (17). p Values less than 0.01 for the comparison between each sitaxsentan dose (100 and 300 mg) and placebo.

Clinical Worsening
Only four patients had events of clinical worsening as defined in the protocol, i.e., death, epoprostenol use, atrial septostomy, or transplantation, consistent with a high percentage of patients with mild-to-moderate disease at baseline. Clinical worsening at Week 12 occurred in 3/60 (5%) patients in the placebo group, in none of the 55 patients in the sitaxsentan 100-mg group, and in 1/63 (2%) patient in the sitaxsentan 300-mg group. No significant differences were seen between treatment groups in time to clinical worsening.

Pharmacokinetics
Comparison of the maximum-concentration-of-drug (C_max) and area-under- curve for Days 2 (AUC) and 84 (AUC_0–24) indicates significant accumulation of sitaxsentan over the dosing period for sitaxsentan 300 mg but not 100 mg. Pharmacokinetic analyses showed that sitaxsentan 100 mg resulted in no increase in mean C_max and a 1.3-fold increase in mean AUC values from baseline to Week 12. In contrast, sitaxsentan 300 mg resulted in a 1.4-fold increase in mean C_max and a 3.1-fold increase in mean AUC values from baseline to Week 12. The ratio of geometric mean values for area under the plasma level–time curve at steady state (AUC_ss) at Week 12 for 300 mg/100 mg was 11.3, reflecting nonlinearity in the elimination of sitaxsentan when administered at a dose of 300 mg.

Safety
No clinically meaningful differences were seen between groups in the total number of adverse events reported or in the incidence of patients with adverse events. The incidence of serious adverse events was infrequent, with no significant differences among treatment groups (placebo, 15%; sitaxsentan 100 mg, 5%; sitaxsentan 300 mg, 16%). One death, judged by the investigator to be due to worsening PAH and unrelated to study drug, occurred in the 300-mg group.

The most frequently reported clinical adverse events with sitaxsentan treatment (and more frequent than with placebo) were headache, peripheral edema, nausea, nasal congestion, and dizziness (Table 4) , reactions previously noted with ET receptor antagonists (7, 8, 18). The most frequently reported laboratory adverse event was increased international normalized ratio or prothrombin time, related to the effect of sitaxsentan on inhibition of CYP2C9 P450 enzyme, the principal hepatic enzyme involved in the metabolism of warfarin (18). The incidence of increased international normalized ratio or prothrombin time was higher in the sitaxsentan 300-mg group versus placebo (p < 0.005) as well as in the combined sitaxsentan 100-mg and 300-mg groups versus placebo (p < 0.02). Observations during the trial showed that this interaction can be managed by reducing the warfarin dose to achieve the desired international normalized ratio.

Modest dose-related changes occurred in serum hemoglobin concentration. Decreases in hemoglobin in sitaxsentan-treated groups were observed as early as Week 2 and remained stable throughout the study (mean change from baseline to Week 12; placebo, 0.2 g/dl; 100 mg, -1.0 g/dl; 300 mg, -1.6 g/dl). None of the hemoglobin changes was clinically significant.

The Data and Safety Monitoring Board did not request data to be unblinded during the two interim safety evaluations and deemed that no change to the conduct of the trial was warranted.

	DISCUSSION

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This trial is the first placebo-controlled multicenter study to evaluate a selective ET_A receptor antagonist, i.e., sitaxsentan, in PAH. Although the 300-mg group met the primary endpoint, i.e., increased peak O₂ compared with placebo, none of the other endpoints derived from CPET, i.e., O₂ at AT and E/CO₂ at AT, were met. However, both the 100 and 300 mg doses, compared with placebo, improved 6-minute walk distance, functional class, cardiac index, and pulmonary vascular resistance. The reasons for the discrepancy between results obtained from CPET versus other measures that have been validated in previous PAH trials (i.e., 6-minute walk test, functional class, pulmonary vascular resistance, and cardiac index) are unclear. However, the possibility of greater technical expertise required to conduct CPET testing, intrasubject variability, and lack of validation of CPET parameters as efficacy endpoints in PAH trials may be important considerations.

The 6-minute walk test has been the most widely used measure of exercise capacity in PAH clinical trials (19) and has shown benefits from treatment with epoprostenol (20), bosentan (7, 8), treprostinil (21), and beraprost (22, 23). We elected to use peak O₂ as the primary endpoint on the basis of the correlation reported between 6-minute walk distance and peak O₂ and literature suggesting that peak O₂ is an independent predictor of survival in patients with idiopathic PAH (24, 25). Despite protocol-specified guidelines for the conduct of CPET testing, it is possible that the discrepancy between 6-minute walk distance and peak O₂ data in the present multicenter study could have been minimized by validation of each center's CPET facilities and use of a core laboratory for data acquisition and interpretation. Alternatively, 6-minute walk distance, i.e., exercise endurance, may be a better index of the ability of a patient with chronic heart and/or lung disease to perform daily activities than peak O₂, i.e., exercise tolerance (26). Interestingly, in a recently published PAH study that also used both the 6-minute walk test and CPET as efficacy endpoints, it is noteworthy that treatment with the active study drug, i.e., beraprost, resulted in significant improvement in 6-minute walk distance at 3 and 6 months, with no associated improvement in peak O₂ (23).

To date, clinical trials in PAH that have used the 6-minute walk test as the primary endpoint have traditionally limited enrollment to those with functional Class III or IV disease, either idiopathic or connective tissue disease etiology, and baseline 6-minute walk distances less than or equal to 450 m (7, 8, 20). In contrast, this trial included patients with PAH with functional Class II disease, congenital heart defects, and baseline 6-minute walk distances more than 450 m. The 6-minute walk distance for patients in this trial (mean ± SD: 398 ± 110 m, range 79–657 m) was 20 to 30% higher than in previous trials with other agents for PAH, (7, 8, 20–22) in part due to inclusion of patients with mild (NYHA Class II) functional status. To evaluate whether a "ceiling effect" masked efficacy, we conducted a post hoc analysis of those patients meeting traditional enrollment criteria, i.e., Class III/IV PAH (idiopathic or related to connective tissue disease) with a baseline 6-minute walk of 450 m or more. For these analyses, although two sitaxsentan doses were evaluated in this trial, i.e., 100 and 300 mg, the data were pooled on the basis of similar treatment effects on the 6-minute walk test, functional class, cardiac index, and pulmonary vascular resistance for both doses (all p < 0.02). Using these traditional enrollment criteria, the treatment effect for 6-minute walk increased from 34 m in the entire STRIDE-1 population to 65 m in the STRIDE-1 patients meeting traditional inclusion criteria. Similarly, the hemodynamic improvement also increased when analyzed in the patients meeting the traditional trial design enrollment criteria compared with the broader inclusion criteria used in this trial. Therefore, patients with functional Class II limitations, PAH related to congenital heart disease, or a baseline 6-minute walk more than 450 m may have a relatively lower treatment effect related to this "masking effect." As a result, comparisons between PAH trials with differing enrollment criteria (7, 8, 19–23) require caution. The advantages of a selective ET_A receptor antagonist, (e.g., sitaxsentan) compared with a combined ET_A and ET_B antagonist (e.g., bosentan) can best be determined in comparator trials.

In summary, although the selective ET_A receptor antagonist, sitaxsentan, did not meet the endpoints derived from CPET (i.e., O₂, O₂ at AT, or E/CO₂ at AT), it did improve 6-minute walk distance, functional class, pulmonary vascular resistance, and cardiac index after 12 weeks of treatment in patients with PAH. The similar effects on the latter efficacy endpoints suggest that significant saturation of ET_A receptors occurred with both sitaxsentan doses. In contrast, the incidence of liver function abnormalities was much lower for the 100-mg dose compared with the 300-mg dose, suggesting a distinct dose response for safety and tolerability. Future trials are needed to confirm efficacy with sitaxsentan in the treatment of PAH as well as to determine the optimal dose on the basis of overall risk–benefit considerations.

	Acknowledgments

 
The authors thank the following additional STRIDE Study Group investigators and their staff members, who enrolled patients at the following institutions: Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada (Andrew Hirsch, Eileen Shalit); Cleveland Clinic Foundation, Cleveland, OH (Alejandro Arroliga, Robert Schilz); Ohio State University Medical Center, Columbus (Curt Daniels); Louisiana State University School of Medicine, New Orleans (Bennett deBoisblanc); University of California, San Francisco (Teresa De Marco); Stanford University Medical Center, Stanford, CA (Ramona Doyle); Massachusetts General Hospital, Boston (Leo Ginns); Johns Hopkins Hospital, Baltimore, MD (Reda Girgis); Medical College of Georgia, Augusta (James Gossage); Children's Hospital, Denver, CO (Dunbar Ivy); Mayo Clinic, Rochester, MN (Sudhir Kushwaha); University of Pittsburgh Medical Center, Pittsburgh, PA (Srinivas Murali); University of Michigan, Ann Arbor (Melvyn Rubenfire); Maine Medical Center, Portland (Joel Wirth); Data and Safety Monitoring Board—Bruce Brundage (Chair), Kanu Chatterjee, Roger Flora, Harold Palevsky; ICOS Corporation—Michael Deeley, Pam Walentynowicz; Encysive Pharmaceuticals—Phil Brown, Bruce Given. The authors also thank William Kramer, Willis Maddrey, and Karlman Wasserman for their expertise and collaboration.

	FOOTNOTES

 
Supported by ICOS Corporation, Bothell, WA, and Encysive Pharmaceuticals, Houston, TX.

Conflict of Interest Statement: R.J.B. has served as a consultant and member of the Advisory Board for Actelion Ltd., Encysive Pharmaceutics, and United Therapeutics Corp. and, in addition, she has been reimbursed for speaking at conferences sponsored by Actelion and received $474,000 during the past three years from Actelion as research grants for participating in multicenter clinical trials and $533,000 in the past three years from Encysive as research grants for participating in multicenter clinical trials and $223,000 in the past three years from United Therapeutics as research grants for participating in multicenter clinical trials; D.L. owns 100 shares of Encysive stock which were purchased and not a gift or payment from the company; A.F. has participated as a speaker in scientific meetings or courses organized and financed by various pharmaceutical companies (MedImmune, Actelion, Intermune) and received $5,000 from Actelion in 2002 and in 2003 as unrestricted education grants and received for consultancy or adviser $1,500 from Actelion and $1,500 from Pfizer in 2002 and 2003, respectively, and received payments as research grants in multiple multicenter national studies of PAH from ICOS, Actelion, Intermune, Pfizer, United Therapeutic, Wyeth Ayerst, and from Novartis in pulmonary, pulmonary vascular, and pulmonary transplant-related studies; E.M.H.'s center received $474,000 during the past three years from Actelion as research grants for participating in multicenter clinical trials and $533,000 in the past three years from Encysive as research grants for participating in multicenter clinical trials and $223,000 in the past three years from United Therapeutics as research grants for participating in multicenter clinical trials; R.O. has no declared conflict of interest; S.S. received funding from ICOS for participation in the study submitted for publication and we are currently planning to be co-investigators for the anticipated study of this drug, comparing it to Tracleer and placebo and the amount received for this study was $230,000 which covered the research, diagnostic studies, etc.; V.M. has received study grants from Actelion, United Therapeutics, Myogen, Pfizer, Texas Biotechnology/ICOS and consulted for Actelion and is on the Advisory Board for United Therapeutics and received lecture fees from Actelion and United Therapeutics; N.H. was an investigator in the sitaxsentian trial presented here and supported by ICOS and has received $5,000 in honoraria from United Therapeutics in the past three years for speaking engagements and $5,000 from Actelion for speaking engagements and has received a research grant for $60,000 from Actelion; V.F.T. has no declared conflict of interest; I.M.R. has no declared conflict of interest; D.Z. has received funds from ICOS-Texas Biotechnology, L.P. sufficient to conduct the clinical trial discussed in this manuscript; B.D. is presently employed by the co-sponsor (ICOS Corporation) who conducted the clinical trial and manufactured sitaxsentan and has been an employee of ICOS Corporation since June 2002 and has been compensated greater than $10,000 during my period of employment and, in addition, presently owns shares of stock and stock options for ICOS Corporation that, in combination, are presently worth greater than $10,000; R.A.F.D. is employed by Encysive Pharmaceuticals who sponsored the study; L.R.F. is an employee of ICOS Corporation.

Received in original form July 14, 2003; accepted in final form November 7, 2003

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