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Safety Issue: The trial was prematurely terminated on Dec 9, 2010, due to safety concerns, specifically new emerging evidence of hepatic injury.
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Sitaxsentan has a low drug-drug interaction potential and it did not have a clinically relevant effect on pharmacokinetics of sildenafil (a CYP3A sensitive substrate and PDE5 inhibitor).
Tadalafil did not have clinically relevant effect on pharmacokinetics of bosentan and ambrisentan. Based on overall clinical drug-drug interaction profiles, and in vitro CYP enzymes and transporter data, a clinically relevant drug-drug interaction between sitaxsentan and tadalafil is not expected. Sildenafil is not expected to affect sitaxsentan pharmacokinetics (PK), as sitaxsentan is a substrate of CYP3A4 and CYP2C9, where sildenafil did not show clinically relevant effect on PK of substrates of CYP3A4 and CYP2C9.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment A | Experimental | sitaxsentan 100 mg QD for 6 days (Treatment A) |
|
| Treatment B | Experimental | tadalafil 40 mg QD for 6 days |
|
| Treatment C | Experimental | sitaxsentan 100 mg QD co-administered with tadalafil 40 mg QD for 6 days |
|
| Treatment D | Experimental | sitaxsentan 100 mg QD co-administered with sildenafil 20 mg TID for 6 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| sitaxentan | Drug | sitaxsentan 100 mg QD for 6 days |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Time to Reach Maximum Observed Plasma Concentration (Tmax) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) | |
| Trough Plasma Concentrations (Ctrough) | Minimum or "trough"concentrations | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| Maximum Observed Plasma Concentration (Cmax) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) | |
| Area Under the Curve of the 24 Hour Dosing Interval (AUC24) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) | |
| Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| Volume of Distribution at Steady State (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| Measure | Description | Time Frame |
|---|---|---|
| Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pfizer Investigational Site | Singapore | 188770 | Singapore |
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| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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The study was terminated for safety reasons (hepatoxicity) after dosing was completed for the first intervention.
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| ID | Title | Description |
|---|---|---|
| FG000 | Sitax, Then Tad, Then Sitax and Tad, Then Sitax and Sild | Sitaxsentan 100 milligram (mg) tablet once daily (QD) for 6 days, then tadalafil 40 mg tablet QD for 6 days, then sitaxsentan 100 mg tablet QD co-administered with tadalafil 40 mg tablet QD for 6 days, then sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg table three times daily (TID) for 6 days. Only the first treatment in the sequence was administered due to the early termination. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| tadalafil | Drug | tadalafil 40 mg QD for 6 days |
|
| sitaxsentan | Drug | sitaxsentan 100 mg QD for 6 days |
|
| tadalafil | Drug | tadalafil 40 mg QD for 6 days |
|
| sitaxsentan | Drug | sitaxentan 100 mg QD for 6 days |
|
| sildenafil | Drug | sildenafil 20 mg TID for 6 days |
|
| FG001 | Tad, Then Sitax and Sild, Then Sitax, Then Sitax and Tad | Tadalafil 40 mg tablet QD for 6 days, then sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg table TID for 6 days, then sitaxsentan 100 mg tablet QD for 6 days, then sitaxsentan 100 mg tablet QD co-administered with tadalafil 40 mg tablet QD for 6 days. Only the first treatment in the sequence was administered due to the early termination. |
| FG002 | Sitax and Tad, Then Sitax, Then Sitax and Sild, Then Tad | Sitaxsentan 100 mg tablet QD co-administered with tadalafil 40 mg tablet QD for 6 days, then sitaxsentan 100 mg tablet QD for 6 days, then sitaxsentan100 mg tablet QD co-administered with sildenafil 20 mg table TID for 6 days, then tadalafil 40 mg tablet QD for 6 days. Only the first treatment in the sequence was administered due to the early termination. |
| FG003 | Sitax and Sild, Then Sitax and Tad, Then Tad, Then Sitax | Sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg table TID for 6 days, then sitaxsentan 100 mg tablet QD co-administered with tadalafil 40 mg tablet QD for 6 days, then tadalafil 40 mg tablet QD for 6 days, then sitaxsentan 100 mg tablet QD for 6 days. Only the first treatment in the sequence was administered due to the early termination. |
| COMPLETED |
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| NOT COMPLETED |
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|
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | All randomized participants |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Mean | Standard Deviation | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Time to Reach Maximum Observed Plasma Concentration (Tmax) | Not analyzed due to early study termination. | Posted | Median | Full Range | hours | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
|
| ||||||||||||||||||||||||||
| Primary | Trough Plasma Concentrations (Ctrough) | Minimum or "trough"concentrations | Not analyzed due to early study termination. | Posted | Geometric Mean | Standard Deviation | nanograms (ng)/milliliter (mL) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| ||||||||||||||||||||||||||
| Primary | Maximum Observed Plasma Concentration (Cmax) | Not analyzed due to early study termination. | Posted | Geometric Mean | Standard Deviation | micrograms per milliliter (mcg/mL) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| |||||||||||||||||||||||||||
| Primary | Area Under the Curve of the 24 Hour Dosing Interval (AUC24) | Not analyzed due to early study termination. | Posted | Geometric Mean | Standard Deviation | nanogram hour per milliliter (ng*hr/mL) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| |||||||||||||||||||||||||||
| Primary | Apparent Oral Clearance (CL/F) | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. | Not analyzed due to early study termination. | Posted | Geometric Mean | Standard Deviation | mL/minute | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| ||||||||||||||||||||||||||
| Secondary | Plasma Decay Half-Life (t1/2) | Plasma decay half-life is the time measured for the plasma concentration to decrease by one half. | Not analyzed due to early study termination. | Posted | Mean | Standard Deviation | hours | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
| ||||||||||||||||||||||||||
| Primary | Volume of Distribution at Steady State (Vss) | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. | Not analyzed due to early study termination. | Posted | Geometric Mean | Standard Deviation | Liter (L) | Day 6 (predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose) |
|
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The same event may appear as both an adverse event (AE) and a serious AE (SAE). However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another subject, or 1 participant may have experienced both a serious and nonserious event during the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Sitaxsentan | Sitaxsentan 100 mg tablet QD for 6 days | 0 | 4 | 1 | 4 | ||
| EG001 | Tadalafil | Tadalafil 40 mg tablet QD for 6 days | 0 | 4 | 4 | 4 | ||
| EG002 | Sitaxsentan and Tadalafil | Sitaxsentan 100 mg tablet QD co-administered with tadalafil 40 mg tablet QD for 6 days | 0 | 4 | 4 | 4 | ||
| EG003 | Sitaxsentan and Sildenafil | Sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg table TID for 6 days | 0 | 4 | 2 | 4 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Abdominal distension | Gastrointestinal disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Dysphagia | Gastrointestinal disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Chills | General disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Feeling abnormal | General disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Dizziness | Nervous system disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Head discomfort | Nervous system disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Somnolence | Nervous system disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA v13.1 | Non-systematic Assessment |
| |
| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA v13.1 | Non-systematic Assessment |
|
Study endpoints were not analyzed due to early termination.
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer, Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
| ID | Term |
|---|---|
| D000081029 | Pulmonary Arterial Hypertension |
| ID | Term |
|---|---|
| D006976 | Hypertension, Pulmonary |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| C106276 | sitaxsentan |
| D000068581 | Tadalafil |
| D000068677 | Sildenafil Citrate |
| ID | Term |
|---|---|
| D002243 | Carbolines |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D026121 | Indole Alkaloids |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D010879 | Piperazines |
| D011687 | Purines |
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|
|
|
| OG003 | Sitaxsentan and Sildenafil | Sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg tablet TID for 6 days during any treatment period. Only the first treatment in the sequence was administered due to the early termination. |
|
Sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg tablet TID for 6 days during any treatment period. Only the first treatment in the sequence was administered due to the early termination.
|
| OG003 |
| Sitaxsentan and Sildenafil |
Sitaxsentan 100 mg tablet QD co-administered with sildenafil 20 mg tablet TID for 6 days during any treatment period. Only the first treatment in the sequence was administered due to the early termination. |
|