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A Phase 1, Open-Label Study of Intravenous Sildenafil in Patients With Cirrhosis

Primary Purpose

Cirrhosis

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
IV bolus injection of Sildenafil
Sponsored by
University of Maryland, Baltimore
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cirrhosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Subjects will be eligible for the study if they meet the following inclusion criteria:

  1. Cirrhosis. Diagnosis of cirrhosis will be based on either liver biopsy OR clinical characteristics (e.g. history of ascites or encephalopathy or esophageal varices or gastric varices or splenomegaly or spider angioma or any clinical sign of portal hypertension/cirrhosis), laboratory (e.g. history of thrombocytopenia or history of APRI (Reference: Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518-26) [Aspartate aminotransferase (AST) to platelet ratio index] score consistent with cirrhosis or history of abnormal liver function tests) and abdominal imaging (Magnetic Resonance Imaging or Computed Tomography or ultrasound of the abdomen) data
  2. CTP Class B or C cirrhosis
  3. Age 18 years or older at the time of enrollment
  4. Variceal screening with an upper endoscopy within 1 year before enrollment
  5. Renal dysfunction [GFR ≥ 15 and < 60 ml/min/1.73m2 estimated by 6-variable MDRD equation (Reference: Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-54)]
  6. Hemoglobin level ≥ 8 mg/dl within 4 weeks before enrollment
  7. Serum sodium level ≥ 125 mmol/L within 4 weeks before enrollment

Subjects will be excluded if they have any of the following:

  1. Inability to provide informed consent
  2. Women who are pregnant, breast-feeding, or contemplating pregnancy
  3. Treatment with organic nitrates, ritonavir, erythromycin, saquinavir, ketoconazole, itraconazole, cimetidine, bosentan, rifampin, Sildenafil or any other PDE-5 inhibitors, alpha-blockers, and anticoagulants within 7 days before enrollment
  4. Hypersensitivity or allergy to Sildenafil or any component of Sildenafil
  5. Previous reaction to PDE-5 inhibitors including, but not limited to Sildenafil, Vardenafil, Tadalafil, Avanafil (Myocardial infarction, ventricular arrhythmia, sudden cardiac death, cerebrovascular hemorrhage, transient ischemic attack, stroke, transient global amnesia, subarachnoid and intracerebral hemorrhages, seizure, recurrence in seizures, pulmonary hemorrhage, sudden decrease of hearing, loss of hearing, anxiety, prolonged erection, priapism, ocular redness, ocular burning, diplopia, temporary vision loss/decreased vision, ocular swelling, ocular pressure, increased intraocular pressure, retinal problems in the eye, vitreous detachment, vitreous traction, paramacular edema, non-arteritic anterior ischemic optic neuropathy)
  6. History of untreated severe left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis)
  7. History of pulmonary veno-occlusive disease
  8. History of unstable angina, myocardial infarctus, life-threatening arrhythmia or stroke within 6 months before enrollment
  9. History of retinitis pigmentosa
  10. Anatomical deformation of the penis (Peyronie's disease, angulation, cavernosal fibrosis)
  11. History of sickle cell anemia, multiple myeloma or leukemia
  12. Renal failure treated with dialysis
  13. Cognitive impairment based on IRB "evaluation to sign consent form"
  14. Transjugular intrahepatic porto-systemic shunt placement
  15. Previous kidney or liver transplantation

Sites / Locations

  • University of Maryland, Baltimore

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

IV bolus injection of Sildenafil

Arm Description

CTP class B cirrhosis: A single 5 and 10 mg IV bolus injections of Sildenafil. CTP class C cirrhosis: A single 2.5, 5, 8 and 10 mg IV bolus injections of Sildenafil.

Outcomes

Primary Outcome Measures

Number of participants with "suspected adverse reaction" of IV Sildenafil that is both "serious" and "unexpected" as a measure of safety and tolerability.

Secondary Outcome Measures

Full Information

First Posted
September 13, 2013
Last Updated
November 9, 2022
Sponsor
University of Maryland, Baltimore
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1. Study Identification

Unique Protocol Identification Number
NCT01954524
Brief Title
A Phase 1, Open-Label Study of Intravenous Sildenafil in Patients With Cirrhosis
Official Title
A Phase 1, Open-Label Study of Intravenous Sildenafil in Patients With Cirrhosis
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Terminated
Why Stopped
The study is closed due to lack of funding to support the study.
Study Start Date
May 2014 (undefined)
Primary Completion Date
October 2015 (Actual)
Study Completion Date
October 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Maryland, Baltimore

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Safety and tolerability of a single dose intravenous bolus injection of Sildenafil in patients with moderate to severe cirrhosis and kidney disease will be determined.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IV bolus injection of Sildenafil
Arm Type
Experimental
Arm Description
CTP class B cirrhosis: A single 5 and 10 mg IV bolus injections of Sildenafil. CTP class C cirrhosis: A single 2.5, 5, 8 and 10 mg IV bolus injections of Sildenafil.
Intervention Type
Drug
Intervention Name(s)
IV bolus injection of Sildenafil
Other Intervention Name(s)
Revatio
Intervention Description
Dose escalation will be performed (in different participants). The doses will be as follows: CTP class B cirrhosis: A single 5 and 10 mg IV bolus injections of Sildenafil. CTP class C cirrhosis: A single 2.5, 5, 8 and 10 mg IV bolus injections of Sildenafil.
Primary Outcome Measure Information:
Title
Number of participants with "suspected adverse reaction" of IV Sildenafil that is both "serious" and "unexpected" as a measure of safety and tolerability.
Time Frame
The total time to assess the primary outcome measure will be 48 hours after Sildenafil injection (starting from Sildenafil injection time until 48 hours after Sildenafil injection).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Subjects will be eligible for the study if they meet the following inclusion criteria: Cirrhosis. Diagnosis of cirrhosis will be based on either liver biopsy OR clinical characteristics (e.g. history of ascites or encephalopathy or esophageal varices or gastric varices or splenomegaly or spider angioma or any clinical sign of portal hypertension/cirrhosis), laboratory (e.g. history of thrombocytopenia or history of APRI (Reference: Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, Lok AS. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 2003;38:518-26) [Aspartate aminotransferase (AST) to platelet ratio index] score consistent with cirrhosis or history of abnormal liver function tests) and abdominal imaging (Magnetic Resonance Imaging or Computed Tomography or ultrasound of the abdomen) data CTP Class B or C cirrhosis Age 18 years or older at the time of enrollment Variceal screening with an upper endoscopy within 1 year before enrollment Renal dysfunction [GFR ≥ 15 and < 60 ml/min/1.73m2 estimated by 6-variable MDRD equation (Reference: Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145:247-54)] Hemoglobin level ≥ 8 mg/dl within 4 weeks before enrollment Serum sodium level ≥ 125 mmol/L within 4 weeks before enrollment Subjects will be excluded if they have any of the following: Inability to provide informed consent Women who are pregnant, breast-feeding, or contemplating pregnancy Treatment with organic nitrates, ritonavir, erythromycin, saquinavir, ketoconazole, itraconazole, cimetidine, bosentan, rifampin, Sildenafil or any other PDE-5 inhibitors, alpha-blockers, and anticoagulants within 7 days before enrollment Hypersensitivity or allergy to Sildenafil or any component of Sildenafil Previous reaction to PDE-5 inhibitors including, but not limited to Sildenafil, Vardenafil, Tadalafil, Avanafil (Myocardial infarction, ventricular arrhythmia, sudden cardiac death, cerebrovascular hemorrhage, transient ischemic attack, stroke, transient global amnesia, subarachnoid and intracerebral hemorrhages, seizure, recurrence in seizures, pulmonary hemorrhage, sudden decrease of hearing, loss of hearing, anxiety, prolonged erection, priapism, ocular redness, ocular burning, diplopia, temporary vision loss/decreased vision, ocular swelling, ocular pressure, increased intraocular pressure, retinal problems in the eye, vitreous detachment, vitreous traction, paramacular edema, non-arteritic anterior ischemic optic neuropathy) History of untreated severe left ventricular outflow obstruction (e.g. aortic stenosis, idiopathic hypertrophic subaortic stenosis) History of pulmonary veno-occlusive disease History of unstable angina, myocardial infarctus, life-threatening arrhythmia or stroke within 6 months before enrollment History of retinitis pigmentosa Anatomical deformation of the penis (Peyronie's disease, angulation, cavernosal fibrosis) History of sickle cell anemia, multiple myeloma or leukemia Renal failure treated with dialysis Cognitive impairment based on IRB "evaluation to sign consent form" Transjugular intrahepatic porto-systemic shunt placement Previous kidney or liver transplantation
Facility Information:
Facility Name
University of Maryland, Baltimore
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
26143343
Citation
Mindikoglu AL, Dowling TC, Schaub DJ, Hutson WR, Potosky DR, Christenson RH, Barth RN, LaMattina JC, Hanish SI, Weir MR, Raufman JP. Pharmacokinetics and Tolerability of Intravenous Sildenafil in Two Subjects with Child-Turcotte-Pugh Class C Cirrhosis and Renal Dysfunction. Dig Dis Sci. 2015 Nov;60(11):3491-4. doi: 10.1007/s10620-015-3771-0. Epub 2015 Jul 5.
Results Reference
derived

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A Phase 1, Open-Label Study of Intravenous Sildenafil in Patients With Cirrhosis

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