Sitaxsentan Efficacy And Safety Trial With A Randomized Prospective Assessment Of Adding Sildenafil (SR-PAAS)

• Sponsor: Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00795639
• Collaborator: (none)
• Enrollment: 183
• Locations: 85
• Arms: 2
• Duration (Months): 26.9
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This protocol is for subjects with pulmonary arterial hypertension and is the first of 3 studies forming the Sitaxsentan efficacy and safety trial with Randomized Prospective Assessment of Adding Sildenafil (SR-PAAS) program.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension; Pulmonary Hypertension	Drug: Sitaxsentan; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 183 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Safety And Efficacy Study Of Sitaxsentan Sodium In Subjects With Pulmonary Arterial Hypertension
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitaxsentan Monotherapy	Drug: Sitaxsentan; Sitaxsentan = 100 mg tablet administered orally, once daily
Placebo Comparator: Sitaxsentan Placebo Monotherapy	Drug: Placebo; Sitaxsentan Placebo = 1 tablet administered orally, once daily; Other Names: Sitaxsentan Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12 [Baseline/Day 1 and Week 12]

   6 MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety. Change is Week 12 results minus baseline results.

Secondary Outcome Measures

1. Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12 [Baseline, Weeks 4, 8 and 12 or Early Termination (ET)]

   WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Improvement = reduction in functional class, deterioration = increase in functional class, no change = no change in functional class.

2. Time to Clinical Worsening (TTCW) [Baseline, Weeks 4, 8 and 12 or ET]

   TTCW defined as the number of days between first dose of study drug and the occurrence of a predefined clinical worsening event. Predefined clinical worsening events included: hospitalization for worsening PAH, on-study death, heart-lung or lung transplant, atrial septostomy or withdrawal due to the addition of any chronic medications for the treatment of worsening PAH.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Current diagnosis of symptomatic pulmonary arterial hypertension (PAH) classified by one of the following: idiopathic arterial hypertension (IPAH), primary pulmonary hypertension (PPH), familial pulmonary arterial hypertension (FPAH) or pulmonary arterial hypertension (PAH) associated with connective tissue diseases. Has WHO functional class III symptoms.

Exclusion Criteria:

• Previous exposure to an endothelin receptor antagonist (ETRA) such as sitaxsentan, bosentan or ambrisentan.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Fountain Valley	California	United States	92708
2	Pfizer Investigational Site	Mather	California	United States	95655
3	Pfizer Investigational Site	Sacramento	California	United States	95817
4	Pfizer Investigational Site	Englewood	Colorado	United States	80113
5	Pfizer Investigational Site	Littleton	Colorado	United States	80120
6	Pfizer Investigational Site	Gainesville	Florida	United States	32610
7	Pfizer Investigational Site	Sarasota	Florida	United States	34233
8	Pfizer Investigational Site	Weston	Florida	United States	33331
9	Pfizer Investigational Site	Chicago	Illinois	United States	60612
10	Pfizer Investigational Site	Olathe	Kansas	United States	66061
11	Pfizer Investigational Site	Towson	Maryland	United States	21204
12	Pfizer Investigational Site	Boston	Massachusetts	United States	02111
13	Pfizer Investigational Site	Omaha	Nebraska	United States	68131
14	Pfizer Investigational Site	New Brunswick	New Jersey	United States	08903
15	Pfizer Investigational Site	Islandia	New York	United States	11749
16	Pfizer Investigational Site	Stony Brook	New York	United States	11794
17	Pfizer Investigational Site	Chapel Hill	North Carolina	United States	27599
18	Pfizer Investigational Site	Cincinnati	Ohio	United States	45219
19	Pfizer Investigational Site	Cleveland	Ohio	United States	44106
20	Pfizer Investigational Site	Lancaster	Pennsylvania	United States	17602
21	Pfizer Investigational Site	Lancaster	Pennsylvania	United States	17603
22	Pfizer Investigational Site	Philadelphia	Pennsylvania	United States	19140
23	Pfizer Investigational Site	Pittsburgh	Pennsylvania	United States	15212
24	Pfizer Investigational Site	Providence	Rhode Island	United States	02903
25	Pfizer Investigational Site	Charleston	South Carolina	United States	29425
26	Pfizer Investigational Site	Dallas	Texas	United States	75390
27	Pfizer Investigational Site	Houston	Texas	United States	77030
28	Pfizer Investigational Site	San Antonio	Texas	United States	78229
29	Pfizer Investigational Site	Temple	Texas	United States	76508
30	Pfizer Investigational Site	Lynchburg	Virginia	United States	24501
31	Pfizer Investigational Site	Richmond	Virginia	United States	23225
32	Pfizer Investigational Site	Milwaukee	Wisconsin	United States	53215
33	Pfizer Investigational Site	Buenos Aires		Argentina	C1039AAO
34	Pfizer Investigational Site	Buenos Aires		Argentina	C1428DCO
35	Pfizer Investigational Site	Buenos Aires		Argentina	C1428DUS
36	Pfizer Investigational Site	Buenos Aires		Argentina	C1431FWO
37	Pfizer Investigational Site	Sofia		Bulgaria	1202
38	Pfizer Investigational Site	Sofia		Bulgaria	1233
39	Pfizer Investigational Site	Veliko Turnovo		Bulgaria	5000
40	Pfizer Investigational Site	Temuco		Chile	4781173
41	Pfizer Investigational Site	Changsha	Hunan	China	410008
42	Pfizer Investigational Site	Xi'an	Shanxi	China	710032
43	Pfizer Investigational Site	Beijing		China	100032
44	Pfizer Investigational Site	Shanghai		China	200001
45	Pfizer Investigational Site	Shanghai		China	200433
46	Pfizer Investigational Site	Bogotá	Cundinamarca	Colombia
47	Pfizer Investigational Site	Escazu	San Jose	Costa Rica	00000
48	Pfizer Investigational Site	Praha 2		Czech Republic	128 08
49	Pfizer Investigational Site	Santo Domingo	República Dominicana	Dominican Republic	00000
50	Pfizer Investigational Site	Santo Domingo		Dominican Republic	4966
51	Pfizer Investigational Site	Guatemala		Guatemala
52	Pfizer Investigational Site	Hyderabad	Andhera Pradesh	India	500 063
53	Pfizer Investigational Site	Hyderabad	Andhra Pradesh	India	500 001
54	Pfizer Investigational Site	Ahmedabad	Gujarat	India	380 060
55	Pfizer Investigational Site	Surat	Gujarat	India	395 007
56	Pfizer Investigational Site	Vadodara	Gujarat	India	390 015
57	Pfizer Investigational Site	Pune	Maharashtra	India	411 030
58	Pfizer Investigational Site	Coimbatore	Tamil Nadu	India	641 014
59	Pfizer Investigational Site	Madurai	Tamil Nadu	India	625 107
60	Pfizer Investigational Site	Georgetown	Penang	Malaysia	10990
61	Pfizer Investigational Site	Mexico	DF	Mexico	14000
62	Pfizer Investigational Site	Mexico	DF	Mexico	14080
63	Pfizer Investigational Site	Monterrey	Nuevo Leon	Mexico	64718
64	Pfizer Investigational Site	Lima		Peru	13
65	Pfizer Investigational Site	Lima		Peru	32
66	Pfizer Investigational Site	Quezon City		Philippines	1100
67	Pfizer Investigational Site	Cluj Napoca		Romania	400 001
68	Pfizer Investigational Site	Iasi		Romania	700 503
69	Pfizer Investigational Site	Moscow		Russian Federation	105077
70	Pfizer Investigational Site	Moscow		Russian Federation	121552
71	Pfizer Investigational Site	Saint-Petersburg		Russian Federation	194156
72	Pfizer Investigational Site	Saint-Petersburg		Russian Federation	197022
73	Pfizer Investigational Site	Saint-Petersburg		Russian Federation	197341
74	Pfizer Investigational Site	Riyadh		Saudi Arabia	11159
75	Pfizer Investigational Site	Belgrade		Serbia	11000
76	Pfizer Investigational Site	Bratislava		Slovakia	83348
77	Pfizer Investigational Site	Cape Town	Western Cape	South Africa	7531
78	Pfizer Investigational Site	Cape Town		South Africa	7500
79	Pfizer Investigational Site	Johannesburg		South Africa	2193
80	Pfizer Investigational Site	Stellenbosch		South Africa	7600
81	Pfizer Investigational Site	Bangkoknoi	Bangkok	Thailand	10700
82	Pfizer Investigational Site	Bangkok		Thailand	10330
83	Pfizer Investigational Site	Istanbul, Fatih		Turkey	34080
84	Pfizer Investigational Site	Kyiv		Ukraine	03680
85	Pfizer Investigational Site	Kyiv		Ukraine

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00795639
• Other Study ID Numbers: B1321001
• First Posted: Nov 21, 2008
• Last Update Posted: Mar 24, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Pfizer: Sitaxsentan; endothelin receptor antagonist
• Additional relevant MeSH terms: Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Sitaxsentan

Study Results

Participant Flow

Arm/Group Title	Sitaxsentan	Placebo
Arm/Group Description	Sitaxsentan 100 milligrams (mg) tablet orally once a day	Matching placebo tablet once a day
Period Title: Overall Study
STARTED	91	92
Randomized and Not Treated	0	1
COMPLETED	70	66
NOT COMPLETED	21	26

Baseline Characteristics

Arm/Group Title	Sitaxsentan	Placebo	Total
Arm/Group Description	Sitaxsentan 100 milligrams (mg) tablet orally once a day	Matching placebo tablet once a day	Total of all reporting groups
Overall Participants	91	91	182
Age, Customized (participants) [Number]
less than 18 years	0 0%	3 3.3%	3 1.6%
18 to 44 years	53 58.2%	53 58.2%	106 58.2%
45 to 64 years	30 33%	26 28.6%	56 30.8%
greater than or equal to 65 years	8 8.8%	9 9.9%	17 9.3%
Sex: Female, Male (Count of Participants)
Female	71 78%	68 74.7%	139 76.4%
Male	20 22%	23 25.3%	43 23.6%
World Health Organization (WHO) Functional Class (Number) [Number]
Functional Class I	0 0%	0 0%	0 0%
Functional Class II	2 2.2%	0 0%	2 1.1%
Functional Class III	88 96.7%	87 95.6%	175 96.2%
Functional Class IV	0 0%	0 0%	0 0%
Functional Class Unknown	1 1.1%	4 4.4%	5 2.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Total Distance Walked During 6 Minute Walk Distance (6MWD) at Week 12
Description	6 MWD was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety. Change is Week 12 results minus baseline results.
Time Frame	Baseline/Day 1 and Week 12

Outcome Measure Data

Analysis Population Description

Intent to treat population (ITT): all participants who were randomized; missing value at Week 12 imputed with last non-missing value, including the non-missing value obtained at early termination based on last observation carried forward (LOCF)

Arm/Group Title	Sitaxsentan	Placebo
Arm/Group Description	Sitaxsentan 100 milligrams (mg) tablet orally once a day	Matching placebo tablet once a day
Measure Participants	91	92
Baseline	343.0	330.5
Change at Week 12	13.0	3.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitaxsentan, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0104
	Comments	Significance test performed using non-parametric analysis of covariance controlling for Baseline 6MWD and PAH etiology and PAH not secondary to a connective tissue disease (other).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	14
	Confidence Interval	(2-Sided) 95%; 3 to 26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Missing value at Week 12 assigned as zero if the subject had a predefined clinical worsening event, otherwise, missing value at Week 12 imputed with the last non-missing 6MWD based on LOCF.

2. Secondary Outcome

Title	Number of Participants With Change From Baseline in World Health Organization (WHO) Functional Classification at Weeks 4, 8 and 12
Description	WHO functional classification for PAH ranges from Class I (no limitation in physical activity, no dyspnea with normal activity) to Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). Improvement = reduction in functional class, deterioration = increase in functional class, no change = no change in functional class.
Time Frame	Baseline, Weeks 4, 8 and 12 or Early Termination (ET)

Outcome Measure Data

Analysis Population Description

ITT; N=number of participants with analyzable data; n=number of participants with analyzable data at the specific time point

Arm/Group Title	Sitaxsentan	Placebo
Arm/Group Description	Sitaxsentan 100 milligrams (mg) tablet orally once a day	Matching placebo tablet once a day
Measure Participants	90	87
Week 4 - Improvement (n=90, 87)	6 6.6%	2 2.2%
Week 4 - No Change (n=90, 87)	83 91.2%	84 92.3%
Week 4 - Deterioration (n=90, 87)	1 1.1%	1 1.1%
Week 8 - Improvement (n=86, 81)	13 14.3%	6 6.6%
Week 8 - No Change (n=86, 81)	72 79.1%	73 80.2%
Week 8 - Deterioration (n=86, 81)	1 1.1%	2 2.2%
Week 12 - Improvement (n=80, 72)	17 18.7%	7 7.7%
Week 12 - No Change (n=80, 72)	63 69.2%	64 70.3%
Week 12 - Deterioration (n=80, 72)	0 0%	1 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitaxsentan, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2908
	Comments	Significance tests of WHO Functional Class performed using the Cochran-Mantel-Haenszel (CMH) test, stratified by Baseline 6MWD (less than 310 meters and greater than or equal to 310 meters) and PAH Etiology (Connective Tissue Disease and others).
	Method	Cochran-Mantel-Haenszel
	Comments	The CMH test used modified ridit scores, and the p-value corresponding to ANCOVA (row mean scores) statistics were used.

3. Secondary Outcome

Title	Time to Clinical Worsening (TTCW)
Description	TTCW defined as the number of days between first dose of study drug and the occurrence of a predefined clinical worsening event. Predefined clinical worsening events included: hospitalization for worsening PAH, on-study death, heart-lung or lung transplant, atrial septostomy or withdrawal due to the addition of any chronic medications for the treatment of worsening PAH.
Time Frame	Baseline, Weeks 4, 8 and 12 or ET

Outcome Measure Data

Analysis Population Description

ITT; N=number of participants with analyzable data

Arm/Group Title	Sitaxsentan	Placebo
Arm/Group Description	Sitaxsentan 100 milligrams (mg) tablet orally once a day	Matching placebo tablet once a day
Measure Participants	91	91
Median (Full Range) [days]	NA	NA

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an adverse event (AE) and a serious adverse event (SAE). However, what is presented are distinct events. An event may be categorized as serious in one participant and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Sitaxsentan		Placebo
Arm/Group Description	Sitaxsentan 100 milligrams (mg) tablet orally once a day		Matching placebo tablet once a day
All Cause Mortality
	Sitaxsentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sitaxsentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/91 (9.9%)		12/91 (13.2%)
Blood and lymphatic system disorders
Anaemia	1/91 (1.1%)		0/91 (0%)
Cardiac disorders
Acute myocardial infarction	0/91 (0%)		1/91 (1.1%)
Acute right ventricular failure	0/91 (0%)		1/91 (1.1%)
Arrhythmia	0/91 (0%)		1/91 (1.1%)
Cardiac failure	1/91 (1.1%)		2/91 (2.2%)
Cardiac failure congestive	1/91 (1.1%)		0/91 (0%)
Right ventricular failure	1/91 (1.1%)		1/91 (1.1%)
Gastrointestinal disorders
Upper gastrointestinal haemorrhage	1/91 (1.1%)		0/91 (0%)
General disorders
Chest discomfort	0/91 (0%)		1/91 (1.1%)
Fatigue	0/91 (0%)		1/91 (1.1%)
Sudden cardiac death	2/91 (2.2%)		0/91 (0%)
Hepatobiliary disorders
Hepatic failure	0/91 (0%)		1/91 (1.1%)
Hepatitis	0/91 (0%)		1/91 (1.1%)
Infections and infestations
Respiratory tract infection	0/91 (0%)		1/91 (1.1%)
Sepsis	0/91 (0%)		1/91 (1.1%)
Injury, poisoning and procedural complications
Ankle fracture	0/91 (0%)		1/91 (1.1%)
Investigations
Alanine aminotransferase increased	2/91 (2.2%)		0/91 (0%)
Aspartate aminotransferase increased	2/91 (2.2%)		0/91 (0%)
Blood bilirubin increased	1/91 (1.1%)		0/91 (0%)
International normalised ratio increased	1/91 (1.1%)		0/91 (0%)
Liver function test abnormal	1/91 (1.1%)		0/91 (0%)
Psychiatric disorders
Decreased activity	1/91 (1.1%)		0/91 (0%)
Renal and urinary disorders
Nephritis	0/91 (0%)		1/91 (1.1%)
Renal failure	0/91 (0%)		1/91 (1.1%)
Reproductive system and breast disorders
Cervix haemorrhage uterine	0/91 (0%)		1/91 (1.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/91 (1.1%)		1/91 (1.1%)
Pulmonary embolism	0/91 (0%)		1/91 (1.1%)
Vascular disorders
Deep vein thrombosis	0/91 (0%)		1/91 (1.1%)
Other (Not Including Serious) Adverse Events
	Sitaxsentan		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/91 (25.3%)		24/91 (26.4%)
Gastrointestinal disorders
Vomiting	2/91 (2.2%)		5/91 (5.5%)
General disorders
Chest pain	2/91 (2.2%)		3/91 (3.3%)
Fatigue	1/91 (1.1%)		4/91 (4.4%)
Oedema	3/91 (3.3%)		2/91 (2.2%)
Oedema peripheral	5/91 (5.5%)		8/91 (8.8%)
Investigations
Alanine aminotransferase increased	4/91 (4.4%)		1/91 (1.1%)
Aspartate aminotransferase increased	5/91 (5.5%)		2/91 (2.2%)
Metabolism and nutrition disorders
Decreased appetite	1/91 (1.1%)		4/91 (4.4%)
Hypokalaemia	3/91 (3.3%)		0/91 (0%)
Musculoskeletal and connective tissue disorders
Back pain	4/91 (4.4%)		1/91 (1.1%)
Pain in extremity	1/91 (1.1%)		4/91 (4.4%)
Nervous system disorders
Dizziness	5/91 (5.5%)		2/91 (2.2%)
Headache	3/91 (3.3%)		2/91 (2.2%)
Respiratory, thoracic and mediastinal disorders
Cough	1/91 (1.1%)		3/91 (3.3%)
Dyspnoea	3/91 (3.3%)		7/91 (7.7%)

Limitations/Caveats

Study terminated early.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.