Sorafenib for Hepatopulmonary Syndrome (SHPS)

• ClinicalTrials.gov Identifier: NCT02021929
• Recruitment Status: Terminated
• First Posted: December 27, 2013
• Results First Posted: April 25, 2019
• Last Update Posted: April 25, 2019
• Sponsor: University of Pennsylvania
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of Pennsylvania

Study Description

Brief Summary:

The main purpose of this clinical trial is to determine the safety and effects of the study drug, sorafenib, in adults diagnosed with hepatopulmonary syndrome (HPS). The study will evaluate how well the drug is tolerated and its effect on the level of oxygen in the blood and the function of the lung vessels.

Condition or disease	Intervention/treatment	Phase
Hepatopulmonary Syndrome	Drug: Sorafenib; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Sorafenib in Patients With Hepatopulmonary Syndrome: A Double-Blind Randomized Clinical Trial
• Study Start Date: March 2014
• Actual Primary Completion Date: January 2018
• Actual Study Completion Date: January 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sorafenib; 400 mg (2 capsules) taken by mouth once a day	Drug: Sorafenib; Sorafenib is a kinase inhibitor indicated for the treatment of: Unresectable hepatocellular carcinoma; Advanced renal cell carcinoma; Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment; Other Name: Nexavar
Placebo Comparator: Placebo; 2 capsules taken by mouth once a day	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. Change in Alveolar-arterial Oxygen Gradient Between Sorafenib and Placebo Groups [ Time Frame: Baseline to 12 weeks ]

   Alveolar-arterial oxygen gradient is a calculated measure of oxygenation. It is the difference between the amount of the oxygen in the alveoli and the amount of oxygen in arterial blood.

   Calculation is based on values from an Arterial Blood Gas test. Difference in change in alveolar-arterial oxygen gradient between sorafenib and placebo from baseline to 12 weeks.

Secondary Outcome Measures :

1. Number of Participants With Improvement in Intrapulmonary Shunting From Baseline to 12 Weeks. [ Time Frame: Baseline to 12 weeks ]

   Intrapulmonary shunting is measured based on results from a saline-bubble echo test.

   Number of participants with measured improvement in intrapulmonary shunting from baseline to 12 weeks in the sorafenib and placebo groups

2. Change From Baseline in Percentage of Progenitor Cells (Peripheral Blood Mononuclear Cells or PBMCs) [ Time Frame: Baseline to 12 weeks ]

   Progenitor Cells (Peripheral Blood Mononuclear Cells or PBMCs) are obtained and measured from blood samples collected from each participant.

   Difference in change from baseline to 12 weeks in the Percentage of Progenitor Cells between sorafenib and placebo groups.

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of HPS:

  1. AaPO2 ≥ 15 mm Hg (≥ 20 mm Hg for age > 64 yrs)
  2. Intrapulmonary shunting
  3. Absence of significant restriction (TLC < 70%) or obstruction (FEV1 < 80% & FEV1/FVC < 70%)
  4. Presence of cirrhosis/hepatic fibrosis and/or portal hypertension
• Child-Pugh class A or B liver disease
• Platelet count ≥ 30 ×10e9 per liter
• Hemoglobin ≥ 8.5 g per deciliter
• International normalized ratio ≤ 2.3
• Albumin ≥ 2.8 g per deciliter
• Total bilirubin ≤ 5 mg per deciliter
• Alanine aminotransferase and aspartate aminotransferase ≤ 5 times the upper limit of the normal range
• Serum creatinine ≤ 1.5 times the upper limit of the normal range and not receiving dialysis
• Negative pregnancy test (for women of childbearing potential) at both screening and baseline visits. Post-menopausal women (defined as no menses for one year) and surgically sterilized women are not required to undergo a pregnancy test.
• Subjects (men and women) of childbearing potential must agree to use medically acceptable contraception beginning at the signing of the Informed Consent Form until at least 14 days after the last dose of study drug.
• Age ≥ 21 years
• Ability to provide informed consent

Exclusion Criteria:

• Recent chronic heavy alcohol consumption
• Enrollment in a clinical trial or concurrent use of another investigational drug or device therapy (i.e., outside of study treatment) during, or within 28 days of screening visit
• Current hepatic encephalopathy
• Active infection
• Diagnosis of portopulmonary hypertension
• WHO Class IV functional status
• Congenital long-QT syndrome
• Subjects who have used strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days before randomization
• Subjects who are currently taking Coumadin®(warfarin)

• Active or clinically significant cardiac disease, including:

  1. Active coronary artery disease
  2. Unstable angina (anginal symptoms at rest), new-onset angina within 12 weeks before randomization, or myocardial infarction within 24 weeks before randomization
• Liver or other solid organ transplant recipients
• Expectation of liver transplant within four months of randomization

• Hepatocellular carcinoma that does not meet all of the following criteria:

  1. Single lesion ≤ 3 cm documented by LIRADS criteria
  2. Complete response to ablative therapy (TACE, RFA, alcohol ablation) using the modified RECIST criteria one month after therapy with no more than two treatments
  3. No other lesions develop after initiation of HCC therapy
• Uncontrolled hypertension (systolic pressure >140 mm Hg or diastolic pressure > 90 mm Hg on repeated measurement) despite optimal medical management.
• Any hemorrhage/bleeding event of NCI-Common Toxicity Criteria for Adverse Effects v4.0 Grade 3 or higher within 4 weeks before randomization
• Presence of a non-healing wound, non-healing ulcer, or bone fracture
• Women who are pregnant or breast-feeding
• Major surgery 28 days prior to randomization
• Subjects with any previously untreated or concurrent cancer except cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumor. Subjects surviving a cancer that was curatively treated and without evidence of disease for more than 3 years before randomization are allowed. All cancer treatments (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) must be completed at least 3 years prior to study entry (i.e., signature date of the informed consent form).
• Inability to comply with the protocol and/or not willing or not available for follow-up assessments

Contacts and Locations

Locations

United States, Arizona

Mayo Clinic Arizona

Phoenix, Arizona, United States, 85054

United States, Illinois

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States, 60611

United States, Minnesota

Mayo Clinic - Rochester

Rochester, Minnesota, United States, 55905

United States, New York

Columbia University-NewYork-Presbyterian Hospital

New York, New York, United States, 10032

United States, Pennsylvania

University of Pennsylvania - Perelman Center

Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29424

United States, Texas

University of Texas Health Science Center at Houston Medical School

Houston, Texas, United States, 77030

Sponsors and Collaborators

University of Pennsylvania

National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Steven M Kawut, MD, MS; University of Pennsylvania

  Study Documents (Full-Text)

Documents provided by University of Pennsylvania:

Study Protocol and Statistical Analysis Plan  [PDF] June 10, 2016

More Information

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02021929
• Other Study ID Numbers: 819185; UM1HL116886 ( U.S. NIH Grant/Contract )
• First Posted: December 27, 2013
• Results First Posted: April 25, 2019
• Last Update Posted: April 25, 2019
• Last Verified: April 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Keywords provided by University of Pennsylvania:

Randomized Controlled Trial; Clinical Trial; sorafenib; Hepatopulmonary Syndrome

Additional relevant MeSH terms:

Hepatopulmonary Syndrome; Syndrome; Disease; Pathologic Processes; Liver Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Sorafenib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action