Clinically Significant Portal Hypertension
Conditions
Keywords
portal hypertension, sorafenib
Brief summary
Sorafenib is approved by the US FDA for the treatment of unresectable (can not operate) liver cancer and for renal cell carcinoma. Sorafenib is a drug that inhibits the growth of cancer cells and prevents the formation of new blood vessels that would otherwise help the cancer spread. Studies in experimental animals have shown that sorafenib may also lower portal vein pressure (the pressure of the blood passing from the intestine through the liver.) This study seeks to determine if sorafenib lowers the blood pressure in liver blood vessels (portal vein pressure) in patients with cirrhosis who have high portal vein pressure. The study will also obtain information whether sorafenib is safe in this patient population. Half of the patients will be given sorafenib and half will be given a placebo (a pill without any medicine in it.) This allows a comparison of the reactions of people who take sorafenib to those who do not.
Detailed description
This is a pilot proof-of-concept study that investigates the effect of sorafenib on portal pressure, as determined by the hepatic venous pressure gradient (HVPG), in patients with liver cirrhosis, portal hypertension and unresectable hepatocellular carcinoma (HCC) that has successfully responded to radiofrequency ablation and/or transarterial chemoembolization, and have obtained a complete response. The primary end-point of the study is the change in HVPG observed from baseline to three months after starting treatment with sorafenib. Secondary end-point is safety of sorafenib. The trial is structured as a randomized double blind placebo controlled study. After a three-month period of therapy with sorafenib or placebo (double-blind phase), patients will be given open-label sorafenib for an additional 3-month period (open-label phase). A total of 44 patients will be randomized (in the initial phase) on a 1:1 ratio to sorafenib or placebo. Patients will be followed monthly and HCC follow-up will be according to standards of care. The study will be sponsored by Onyx, who will also provide the treatment medication (sorafenib and placebo)
Interventions
DRUGPlacebo
Placebo Comparator: Placebo
DRUGSorafenib
Sorafenib, 400 mg twice daily
Sponsors
Onyx Therapeutics, Inc.
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
20 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 20-75 years * Cirrhosis diagnosed by liver biopsy or by imaging studies showing a nodular liver, splenomegaly and/or collaterals * HCC proven histologically or diagnosed following the AASLD criteria if biopsy not feasible or refused by the patient * HCC must be unresectable and within UCSF criteria (single tumor ≤ 6.5 cm diameter, or, if multiple lesions, maximum diameter of the largest lesion ≤ 4.5 and total tumor diameter ≤ 8 cm (23)) * CPT score \<9 (that is all Child A and Child B with a score of 7 or 8) * Complete response to treatment with RFA (including that performed laparoscopically) or TACE or a combination of the above as defined by radiologic criteria (hepatoma protocol MRI or CT scan performed 4-6 weeks after the procedure). * No more than two ablative procedures prior to enrollment * Presence of portal hypertension, as defined by HVPG of \>5 mmHg * EGD for variceal screening performed within 6 months of entry into the study unless the patient is already on a stable dose of a non selective beta-blocker (adjusted to obtain a heart rate of 55-60 bpm) or treated with variceal band ligation. * Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment * Women of childbearing potential and men must agree to use adequate contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib. * Signed informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Change in HVPG From Baseline | Three Months | Number of participants with a decrease in HPVG that was \> 10% of baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Subjects randomized to placebo will take two tablets of placebo by mouth twice daily.
Placebo: Placebo Comparator: Placebo | 4 |
| Sorafenib Subjects randomized to Sorafenib will take Sorafenib 400 mg by mouth twice daily.
Sorafenib: Sorafenib, 400 mg twice daily | 5 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Sorafenib | Total |
|---|---|---|---|
| Age, Continuous | 55.98 years STANDARD_DEVIATION 4.7 | 58.78 years STANDARD_DEVIATION 4.25 | 57.38 years STANDARD_DEVIATION 4.48 |
| Region of Enrollment United States | 4 participants | 5 participants | 9 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 5 | 5 / 5 |
| serious Total, serious adverse events | 1 / 5 | 0 / 5 |
Outcome results
Primary
Patients With Change in HVPG From Baseline
Number of participants with a decrease in HPVG that was \> 10% of baseline
Time frame: Three Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Patients With Change in HVPG From Baseline | 1 participants |
| Sorafenib | Patients With Change in HVPG From Baseline | 1 participants |