Symptoms and General Pathology

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Participants will receive RIC during transplant and the initial four post-transplant days. During transplant: first intervention after induction of anesthesia but before commencing surgery and the second at the conclusion of the procedure. After transplant: RIC applied daily during the first four consecutive postoperative days. Pneumatic tourniquet will be used to induce RIC

Each RIC intervention will comprise three cycles of 5 minutes of inflation followed by 5 minutes of deflation of a pneumatic tourniquet placed in mid-thigh.

Remote Ischemic Conditioning (RIC)

Portable Tourniquet System(PTSii, Delfi Medical Innovations, Inc.) used to perform RIC interventions.

Pneumatic tourniquet

Baburao Koneru, MD, MPH

This study will assess the feasibility of lower limb-ischemia induced Remote Ischemic Conditioning (RIC) in the perioperative period before, during, and after Orthotopic Liver Transplantation (OLT). Remote ischemic conditioning will consist of 3 cycles of 5 minutes of lower limb ischemia induced via a mid-thigh pneumatic tourniquet, followed by 5 minutes of reperfusion. Interventions will take place after anesthesia induction but before surgery, at the completion of the procedure, and on the mornings of post-operative days 1-4.

Orthotopic liver transplantation (OLT) is associated with a very high risk of complications. In a recent multi-center study of 450 patients, 79% had at least one complication and 63% had severe (Clavien-Dindo grade III or higher) complications. The number and severity of complications are associated with death within 30 days, hospital length of stay, graft and patient survival. Infections are the most common group of complications, followed by pulmonary, renal and liver graft dysfunction. Interventions that decrease these complications after OLT are likely to improve clinical outcomes.

Remote ischemic conditioning is an innate biological phenomenon wherein a brief single or repetitive ischemic stimulus in an organ or tissue such as skeletal muscle induce protection in remote/distant organs against ischemia and other noxious stimuli. This effect can be induced by inflating a pneumatic tourniquet on a leg or arm for a few minutes (usually 5-10) and subsequently deflating to allow reperfusion. This process is usually repeated 3-4 times to ensure an adequate dose of the conditioning stimulus. The conditioning stimulus could be applied before (Preconditioning), concurrent with (Perconditioning), or soon after the index noxious/ischemic insult (Postconditioning).

The goal of this study is to assess the feasibility, patient acceptance, and safety of RIC in liver recipients. In addition, the investigators will obtain data on posttransplant complications. Information obtained from this study will help guide the design of a future randomized, controlled trial to test the benefit of RIC in liver recipients.

Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers - A Feasibility and Safety Study

Proportion of enrolled liver recipients that complete all 6 remote ischemic conditioning (RIC) interventions.

Median intervention-related pain score during each of the post-operative interventions, in extubated patients who are able to communicate. Using the Numerical Rating Scale (NRS, Ferrieira-Valente MA PAIN Volume 152, 2011), patients were asked to rate their pain following the intervention on a scale of 0-10 with 0 being no pain experienced to 10 as the maximum pain felt.

- Withdrawal of consent due to discomfort/pain in the lower extremity

Percentage of participants who developed Early Allograft Dysfunction (EAD) which is defined as:

* Aspartate Transaminase (AST) or Alanine Transaminase (ALT)\> 2,000 U/L at any point within the first seven post-transplant days, or
* Total Bilirubin (TB) \> 10 mg/dL on postoperative day 7,or
* International Normalized Ratio (INR)\> 1.6 on postoperative day 7.

Percentage of Participants who developed Prolonged Respiratory Insufficiency (PRI) defined as:

* Ventilator support for \>2 postoperative days after transplant, or
* Reintubation after extubation, within 7 days of transplant. Patients who require brief re-intubation for an endoscopic, radiologic, or surgical procedure would not be considered to have PRI if they are extubated within 2 days of the end of the procedure.

Percentage of participants who developed Acute Kidney Injury (AKI)

Based on Kidney Disease - Improving Global Outcomes (KDIGO) criteria, AKI criteria are:

Stage 2:

- 2.0-2.9 fold rise in serum creatinine from baseline

Stage 3:

* \> 3.0 fold rise in serum creatinine from baseline, or
* Serum creatinine of \> 4.0 mg/dL, with an acute (\<48 hours) increase of 0.3 mg/dL in serum creatinine or subacute (\< 7 days) increase in serum creatinine of 0.5 mg/dL, or
* Initiation of renal replacement therapy.

In patients who are receiving dialysis pre-op, time to discontinuation of dialysis, if occurring within 90 days of transplantation.

Percentage of patients with Clavien-Dindo \>/= grade III b complications (Dindo D, Demartines N, Clavien P, Annals of Surgery 2004).

The Clavien-Dindo Complications grade ranges from Grade I (Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions Allowed therapeutic regimens are: drugs as antiemetics, antipyretics, analgetics, diuretics and electrolytes and physiotherapy. This grade also includes wound infections opened at the bedside) to Grade V (Death). Grade IIIb would be any intervention requiring general anesthesia.

In patients with Clavien-Dindo \>/= IIIb complications, number of such complications per patient.

Number of days in ICU post-transplant. Starting at post-op day 0 and ending on the calendar date that the patient is transferred out of ICU, dies, or post-op day 90, whichever is soonest.

Number of days in hospital post-transplant. Starting at post-op day 0 and ending on the calendar date that the patient is leaves the hospital, dies, or post-op day 90, whichever is soonest.

Percentage of patients with functioning allograft at 90 days post-transplant

Percentage of patients alive at 90 days post-transplant

Number of subjects that received fewer than 6 interventions,.

Rutgers, The State University of New Jersey

Professor, Department of Surgery

In addition to the clinical.trials. gov definitions, adverse events will be monitored related to the RIC intervention:

Withdrawal of consent due to discomfort/pain in the lower extremity. Any other adverse event considered by the primary clinical team to be related to the RIC intervention.

Participants will receive RIC during transplant and the initial four post-transplant days. During transplant: first intervention after induction of anesthesia but before commencing surgery and the second at the conclusion of the procedure. After transplant: RIC applied daily during the first four consecutive postoperative days. Pneumatic tourniquet will be used to induce RIC

Remote Ischemic Conditioning (RIC): Each RIC intervention will comprise three cycles of 5 minutes of inflation followed by 5 minutes of deflation of a pneumatic tourniquet placed in mid-thigh.

Pneumatic tourniquet: Portable Tourniquet System(PTSii, Delfi Medical Innovations, Inc.) used to perform RIC interventions.

Remote Ischemic Conditioning (RIC) Group

Subjects in this cohort were chosen via retrospective record review, and selected applying the same inclusion and exclusion criteria as in the RIC cohort. They were chosen consecutively in revere-chronological order that began at the start of the study date. Target ratio of RIC:Controls was 1:2. No matching was performed for age, sex, and model for end stage liver disease (MELD) score.

Historical Control Cohort

Subjects received remote ischemic conditioning

Remote Ischemic Conditioning (RIC) Cohort

Historical control subjects received liver transplants in an earlier period

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Two modifications resulted in a smaller number of subjects. Number of cycles, the duration of each cycle and the number of postoperative interventions were not addressed. Lack of randomization led to historical cohort to evaluate some outcomes.

Participants enrolled to receive RIC during transplant and the initial four post-transplant days and who receive all 6 RIC interventions.Subjects in historical control cohort chosen as described above

Percentage of Participants Completing Entire Intervention Protocol

Unintubated subjects were asked to rate intervention-related pain on a scale from 0-10 for each of the postoperative interventions. The maximum pain score obtained from each subject was recorded and the median score for all subjects was calculated. Scale range from 0 - 10 with 10 indicating highest sensation of pain.

Intervention-related Pain Score

Participants who withdrew consent due to pain from RIC intervention.

Withdrawal of Consent Due to Pain

Denominator for this and other postoperative outcomes except death and complications was 30 due to the exclusion of subject who died prior to transplantation

Percentage of Participants Who Developed Early Allograft Dysfunction (EAD)

Percentage of Participants Who Developed Prolonged Respiratory Insufficiency (PRI)

Percentage of Participants Who Developed Acute Kidney Injury (AKI) Stages 2 or 3

Time to Dialysis Discontinuation

Presence of Clavien-Dindo Grade IIIb or Higher Complications

Clavien-Dindo Grade IIIb or Higher - Number of Complications

Intensive Care Unit (ICU) Length of Stay (LOS)

Hospital LOS

Liver Allograft Survival

Patient Survival

Number of subjects who completed \< 6 interventions

Number of Subjects Not Completing Intervention Protocol

Overall Study

Antineoplastic Agents

Sorafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Nexavar

Robert Pelley, MD

Patients with either histological confirmation or clinical diagnosis who are candidate for orthotopic liver transplant(OLT) will receive Sorafenib 400mg 2 x day (BID) as a neoadjuvant (bridging) treatment until transplant. If patient progresses or falls outside of the Milan criteria on sorafenib patient can be treated per physician's discretion using local therapy. Patient will be followed until 30 days after the orthotopic liver transplant (OLT).

Primary objective:

• To evaluate safety (including possible surgical complication) and feasibility of using sorafenib as neo-adjuvant (bridging therapy) prior to orthotopic liver transplant(OLT).

The primary goal of this pilot study is to assess the safety and feasibility of treating HCC patients with sorafenib prior to OLT, as determined by the number of patients experiencing grade 4 hemorrhaging or bleeding post-operatively.

To achieve these goals a 2-stage accrual design will be used with a maximum accrual goal of 10 patients. Initially 5 patients will be entered on-study. If more than one patient experiences grade 4 hemorrhaging/bleeding following OLT the trial will be closed and sorafenib will not be considered safe and/or feasible. If no patient experiences this event 5 additional patients will be enrolled. At the end of the study sorafenib will be considered safe and feasible in this setting if no patient experience grade 4 hemorrhaging/bleeding following transplant. With this design, and assuming at least 3 of the 5 patients in each cohort undergo OLT, the likelihood of stopping early is \<.04 if the underlying risk hemorrhages/bleeding are low (\<5% each) whereas there is a \>.42 chance of early termination if the risks are substantial (e.g. \>.20 likelihood of dose limiting toxicity and \>.30 likelihood of \>grade 4 hemorrhages/bleeding). Overall the likelihood of accepting or not accepting sorafenib as safe and feasible are \>.84, and \<.16, respectively under these conditions.

Secondary objectives:

* Drop out rate
* Time to progression prior to orthotopic liver transplant (OLT)
* Waiting time.

Pilot Study Sorafenib as Bridge to Orthotopic Liver Transplantation (OLT)

Pilot Study: Safety and Feasibility of Using Sorafenib as Neoadjuvant Treatment Prior to Orthotopic Liver Transplantation (OLT) in Patients With Hepatocellular Carcinoma

To assess the safety and feasibility of treating HCC patients with sorafenib prior to OLT, as determined by the number of patients experiencing grade 4 hemorrhaging needing blood trnasfusion, thrombosis of vascular graft structures, stenosis of vascular anastomosis or biliary leaks or anastomotic biliary stenosis.

A measure of time after being put on transplant list until the disease is beyond Milan's criteria prior to OLT.

This is the rate of subjects who were eligible for liver transplant but drop out secondary to disease progression while awaiting donor organ.

This is number of months from the time patient get listed on the transplant list to the time patient under goes actual liver transplant.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Remote Ischemic Conditioning (RIC) in Recipients of Brain Death Donor Livers - A Feasibility and Safety Study	NCT02635347	Liver Failure Carcinoma, Hepa...	Remote Ischemic... Pneumatic tourn...	18 Years -	Rutgers, The State University of New Jersey
Pilot Study Sorafenib as Bridge to Orthotopic Liver Transplantation (OLT)	NCT01337492	Carcinoma, Hepa...	Nexavar	18 Years -	Case Comprehensive Cancer Center

Spots Global Cancer Trial Database for orthotopic liver transplant