A Long Term Extension Study Evaluating Safety Of Sildenafil Citrate When Used To Treat Pulmonary Arterial Hypertension (PAH) In Children

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00159874
First received: September 8, 2005
Last updated: July 17, 2014
Last verified: July 2014
  Purpose

Active treatment, dose-blinded extension study evaluating the safety and long term efficacy of sildenafil citrate in children with PAH.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: Sildenafil citrate
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter, Long-Term Extension Study to Assess Safety of Oral Sildenafil Citrate In The Treatment Of Subjects Who Have Completed Study A1481131

Resource links provided by NLM:


Further study details as provided by Pfizer:

Primary Outcome Measures:
  • Number of Participants Reporting at Least One Adverse Event [ Time Frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation) ] [ Designated as safety issue: Yes ]
    Safety was measured according to standard adverse event collection as described in the adverse event section of the results. Complete tables of the adverse events according to the A1481156 treatment groups are provided in the reported adverse event section.

  • Number of Participants Reporting Treatment-related Adverse Events [ Time Frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation) ] [ Designated as safety issue: Yes ]
    Safety was measured according to standard adverse event collection as described in the adverse event section of the results.

  • Number of Participants Reporting at Least One Serious Adverse Event [ Time Frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation) ] [ Designated as safety issue: Yes ]
    Safety was measured according to standard adverse event collection as described in the adverse event section of the results. Complete tables of the serious adverse events according to the A1481156 treatment groups are provided in the reported adverse event section.

  • Number of Participants Reporting Treatment-related Serious Adverse Events [ Time Frame: Up to Follow-Up visit (30 to 40 days after study completion or treatment discontinuation) ] [ Designated as safety issue: Yes ]
    All serious adverse events regardless of treatment group or suspected relationship to study drug were reported. Investigators were to provide independent determination of possible causality of any serious adverse event.

  • Number of Deaths Reported in the Study Prior to the Data Monitoring Committee (DMC) Recommendation of Dose Down Titration [ Time Frame: Pre-DMC Recommendation dose down titration (04 August 2011) ] [ Designated as safety issue: Yes ]
    Deaths were reported immediately independent of the circumstances or suspected cause at any time during the study through the last follow-up visit or 30 days after the last administration of study drug, whichever comes later.

  • Number of Deaths Reported During This Study [ Time Frame: Last follow-up visit or 30 days after the last administration of study drug ] [ Designated as safety issue: Yes ]
    Deaths were reported immediately independent of the circumstances or suspected cause at any time during the study through the last follow-up visit or 30 days after the last administration of study drug, whichever comes later.

  • Discontinuation Due to Intolerability [ Time Frame: Throughout the treatment duration (median treatment duration 1689 to 1744 days) ] [ Designated as safety issue: Yes ]
    Participant who experienced drug-related intolerance, the participant's dose was reduced by 50%. If, after a dose reduction, the participant continued to appear intolerant, they were discontinued from study treatment.

  • Downtitration in Dose Due to Intolerability. [ Time Frame: Pre-DMC recomendation (04 August 2011) ] [ Designated as safety issue: Yes ]
    Based on review of the survival data, DMC concluded that the high dose of sildenafil was associated with a harmful effect on survival when compared to the low dose. The DMC also expressed concern as to the potential dose-response relationship between increasing dose and mortality. Therefore, on 04 August 2011, the DMC recommended discontinuation of the 40 mg and 80 mg three times a day (TID) doses, as well as the 20 mg TID dose in children with body weight ≤20 kg. The protocol was amended per DMC recommendations.

  • Number of Participants With Deterioration Post Baseline in Visual Acuity Safety Tests [ Time Frame: Week 36 ] [ Designated as safety issue: Yes ]
    Visual Acuity is measured either using the reduced Snellen test or via Teller cards, and was assessed in the left and right eyes separately. There were 9 lines on the reduced Snellen chart which were coded as 6/60, 6/36, 6/24, 6/18, 6/12, 6/9, 6/6, 6/5, 6/4 (where 6/60 was the easiest to read and 6/4 was the most difficult to read). If a participant experienced a visual adverse event the investigator was asked to perform additional ocular assessments either at the visit when the participant reported the visual adverse event or at an unplanned visit.

  • Number of Participants With Deterioration Post Baseline in Color Vision Monitoring Safety Tests. [ Time Frame: Week 36 ] [ Designated as safety issue: Yes ]
    Colour vision was measured where appropriate via the Farnsworth-Munsell D-15 Hue test. This test was performed in both eyes simultaneously or just in a single specific eye. If using a single eye the same eye was used throughout the study. In case of young participants an age-and-ability-appropriate evaluation such as the Ishihara Test for Unlettered Persons were conducted.

  • Pediatric Cognitive Development Status at Week 16. [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
    Participant's cognitive development status was assessed at A1481156 baseline (Week 16 in A1481131; NCT00159913) using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's cognitive development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  • Pediatric Cognitive Development Status at Week 52. [ Time Frame: Week 52 ] [ Designated as safety issue: Yes ]
    Participant's cognitive development status was assessed at Week 52 using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's cognitive development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  • Pediatric Motor Development Status at Week 16. [ Time Frame: Week 16 ] [ Designated as safety issue: Yes ]
    Participant's motor development status was assessed at A1481156 baseline (Week 16 in A1481131; NCT00159913) using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's motor development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.

  • Pediatric Motor Development Status at Week 52 [ Time Frame: Week 52 ] [ Designated as safety issue: Yes ]
    Participant's motor development status was assessed at Week 52 using the physician assessment questions. Assessment question (i.e., compared to other children the participant's age group is this participant's motor development limited?) included the following criteria : severely limited, moderately limited, mildly limited and not limited.


Secondary Outcome Measures:
  • Peak Volume of Oxygen (VO2) Consumed at Year 1 Using a Bicycle Ergometry Cardiopulmonary Exercise Test (CPX) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to determine the peak volume of VO2 consumed. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant

  • Percentage Change From Baseline in Percent Predicted Peak VO2 at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the percent predicted peak VO2 at Week 16 and Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.

  • Percent Change From Baseline in Time to Maximum VO2 at Year 1 [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to determine the time to maximum VO2. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.

  • Percent Change From Baseline in Respiratory Exchange Ratio at Year 1 [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    This is the ratio of carbon dioxide (CO2) produced to O2 consumed [VCO2/VO2]. Exercise Tolerance Test was performed on developmentally able participants to determine the respiratory exchange ratio on week 16 and Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913).

  • Percent Change From Start of Sildenafil in Total Ventilation (VE) to Year 1 [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to determine the total ventilation. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.

  • Percentage Change From Baseline in End Tidal Oxygen (O2) at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the End Tidal O2 at Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.

  • Percentage Change From Baseline in End Tidal Carbon Dioxide (CO2) at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the End Tidal CO2 at Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.

  • Percentage Change From Baseline in Anaerobic Threshold at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    Exercise Tolerance Test (CPX test) was performed on developmentally able participants to measure the anaerobic threshold at Week 16 and Year 1. Participants were assumed to be developmentally able if they had a CPX exercise assessment at any visit during study A1481131 (NCT00159913). The CPX tests were performed as close to trough plasma levels of sildenafil as possible, i.e., prior to dosing and at least 4 hours after the previous dose. If participants were able to perform the CPX test in Study A1481131 (NCT00159913), they were expected to be able to perform the exercise paradigm in the extension study (A1481156) unless their clinical condition had deteriorated and the investigator considered this was unsafe for the participant.

  • Summary of Shift in Changes From Start of Sildenafil in World Health Organization Pulmonary Hypertension (WHO PH) Functional Class by A1481156 Treatment Group at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarized at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated.

  • Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 2. [ Time Frame: Baseline, Year 2 ] [ Designated as safety issue: No ]
    The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated.

  • Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 3. [ Time Frame: Baseline, Year 3 ] [ Designated as safety issue: No ]
    The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 (NCT00159913) baseline at Years 1, 2, 3 and 4 were evaluated.

  • Summary of Shift in Changes From Start of Sildenafil in WHO PH Functional Class by A1481156 Treatment Group at Year 4. [ Time Frame: Baseline, Year 4 ] [ Designated as safety issue: No ]
    The WHO PH functional classification was as follows: Class I : Participants with PH but without resulting limitation of physical activity. Class II : Participants with PH resulting in slight limitation of physical activity. Class III : Participants with PH resulting in marked limitation of physical activity. Class IV : Participants with PH with inability to carry out any physical activity without symptoms. Changes from baseline in functional class were summarised at Years 1, 2, 3, and 4. Numbers of participants improving by 3 classes, improving by 2 classes, improving by 1 class, not changing, worsening by 1 class, worsening by 2 classes or worsening by 3 classes from A1481131 baseline at Years 1, 2, 3 and 4 were evaluated.

  • Additions From Baseline in Background Therapy up to the End of Study [ Time Frame: Up to the end of study ] [ Designated as safety issue: No ]
    This was defined as an addition or discontinuation in the class(es) of drugs used as background medication (e.g., anticoagulants, oxygen, diuretics, calcium channel blockers, and digoxin) compared to baseline of Study A1481131 (NCT00159913).

  • Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Psychosocial Scale at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    CHQ: 50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being, and relative burden of disease on the parents; rated on Likert-type scale: range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms (transformed scores); range 0 to 100: higher scores indicate more positive health status.

  • Change From Baseline in Child Health Questionnaire-Parent Form (CHQ-PF28) as Assessed by the Physical Scale at Year 1. [ Time Frame: Baseline, Year 1 ] [ Designated as safety issue: No ]
    CHQ: 50-item, 15 subscale parent or legal guardian assessed instrument of child's physical, emotional, social well-being, and relative burden of disease on the parents; rated on Likert-type scale: range 0 to 100; higher scores indicate a more positive health status. Global indicators for Physical Health and Psychosocial Health are weighted composites derived from subscale items using scoring algorithms (transformed scores); range 0 to 100: higher scores indicate more positive health status.

  • Participant (Parent) Global Assessment at Year 1 [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    The participant (parent) global assessment of disease severity was assessed at Year 1 in this extension study. The number and percentage of participants markedly improved, moderately improved, mild improvement, no change, slightly worse, moderately worse, markedly worse were evaluated. Participants who withdrew from study treatment after at least 10 weeks of treatment were requested to perform the global assessments.

  • Physician Global Assessment at Year 1 [ Time Frame: Year 1 ] [ Designated as safety issue: No ]
    The physician global assessment of disease severity was assessed at Year 1 in this extension study. The number and percentage of participants with markedly improved, moderately improved, mild improvement, no change, slightly worse, moderately worse, markedly worse were evaluated. Participants who withdrew from study treatment after at least 10 weeks of treatment were requested to perform the global assessments.


Enrollment: 234
Study Start Date: January 2004
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sildenafil high dose
As per Protocol Amendment 8 (Aug 2011), all doses in the high dose treatment group were discontinued. Subjects who were receiving these doses and continued in the study were requested to down titrate.
Drug: Sildenafil citrate
Oral, subjects with body weight ≥8 - 20 kg: 20 mg 3 times a day (tid) subjects with body weight >20 - 45 kg: 40 mg 3 times a day (tid) subjects with body weight >45 kg: 80 mg 3 times a day (tid)
Experimental: Sildenafil Low dose Drug: Sildenafil citrate
Oral,10 mg 3 times a day (tid), only subjects with body weight >20 kg
Experimental: Sildenafil medium dose
As per Protocol Amendment 8 (August 2011), the dose 40 mg TID in the medium dose treatment group was discontinued. Subjects who were receiving this dose and continued in the study were requested to down titrate.
Drug: Sildenafil citrate
Oral, subjects with body weight ≥8 - 20 kg: 10 mg 3 times a day (tid); subjects with body weight >20 - 45 kg: 20 mg 3 times a day (tid); subjects with body weight >45 kg: 40 mg 3 times a day (tid)

  Eligibility

Ages Eligible for Study:   1 Year to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must complete the 16 Week double-blind efficacy study A1481131.

Exclusion Criteria:

  • Any patient who did not complete Study A1481131.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00159874

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Locations
United States, California
Pfizer Investigational Site
Palo Alto, California, United States, 34304
Pfizer Investigational Site
Palo Alto, California, United States, 94305
Pfizer Investigational Site
Stanford, California, United States, 94305
United States, Colorado
Pfizer Investigational Site
Aurora, Colorado, United States, 80045
United States, Massachusetts
Pfizer Investigational Site
Boston, Massachusetts, United States, 02115
United States, Michigan
Pfizer Investigational Site
Ann Arbor, Michigan, United States, 48109
United States, Missouri
Pfizer Investigational Site
St. Louis, Missouri, United States, 63110
United States, New York
Pfizer Investigational Site
New York, New York, United States, 10032
United States, Ohio
Pfizer Investigational Site
Columbus, Ohio, United States, 43205
United States, South Carolina
Pfizer Investigational Site
Charleston, South Carolina, United States, 29425
United States, Washington
Pfizer Investigational Site
Seattle, Washington, United States, 98105
Brazil
Pfizer Investigational Site
Sao Paulo, SP, Brazil, 04012-909
Pfizer Investigational Site
São Paulo, SP, Brazil, 04023-062
Chile
Pfizer Investigational Site
Puente Alto, Santiago, Chile
Colombia
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Medellin, Antioquia, Colombia
Pfizer Investigational Site
Bogota, Cundinamarca, Colombia
Guatemala
Pfizer Investigational Site
Guatemala, Guatemala
Hungary
Pfizer Investigational Site
Budapest, Hungary, 1083
Pfizer Investigational Site
Budapest, Hungary, 1096
Pfizer Investigational Site
Szeged, Hungary, 6720
India
Pfizer Investigational Site
Hyderabad, Andhra Pradesh, India, 500 001
Pfizer Investigational Site
Hyderabad, Andhra Pradesh, India, 500 073
Pfizer Investigational Site
Kochi, Kerala, India, 682 041
Italy
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Bologna, Italy, 40138
Japan
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Tokyo, Japan
Malaysia
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Penang, Malaysia, 10900
Pfizer Investigational Site
Penang, Malaysia, 10050
Pfizer Investigational Site
Penang, Malaysia, 11600
Mexico
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Mexico, DF, Mexico, 14080
Poland
Pfizer Investigational Site
Krakow, Poland, 30-663
Pfizer Investigational Site
Ruda Slaska, Poland, 41-703
Pfizer Investigational Site
Warszawa, Poland, 04-730
Pfizer Investigational Site
Zabrze, Poland, 41-800
Russian Federation
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Moscow, Russian Federation, 115478
Pfizer Investigational Site
Moscow, Russian Federation, 125412
Sweden
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Lund, Sweden, 221 85
Taiwan
Pfizer Investigational Site
Kaohsiung, Taiwan, 81346
Pfizer Investigational Site
Taipei, Taiwan, 100
Pfizer Investigational Site
Taipei, Taiwan, 11217
Sponsors and Collaborators
Pfizer
Investigators
Study Director: Pfizer CT.gov Call Center Pfizer
  More Information

Additional Information:
No publications provided by Pfizer

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT00159874     History of Changes
Other Study ID Numbers: A1481156
Study First Received: September 8, 2005
Results First Received: December 19, 2013
Last Updated: July 17, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Pfizer:
children

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Citric Acid
Sildenafil
Anticoagulants
Cardiovascular Agents
Chelating Agents
Enzyme Inhibitors
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Sequestering Agents
Therapeutic Uses
Urological Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on October 20, 2014