Trial Information

A2ALL: Adult-to-Adult Living Transplant Cohort Study

The procedure of adult-to-adult living donor liver transplant (LDLT) is an extraordinary
surgical therapy that involves the removal of 70% of the volume mass of an adult donor liver
and its implantation into an adult recipient. A critical shortage of deceased donor livers,
resulting in premature mortality among candidates in need of liver transplantation, remained
the single most compelling force driving the need for adult-to-adult LDLT. Patients
awaiting living donor liver transplant will be asked to enroll in this protocol at the time
of identification of a potential living liver donor. Donors identified for the living
donation will also be asked to enroll in the protocol. Donors and recipients who have
already participated in a liver donation/transplant will be approached to join the protocol
based on their clinical history.

Optimizing donors' health-related quality of life is a foremost goal for liver donor liver
transplant programs and an overarching aim for this study. The proposed A2ALL-2 Health
Related Quality of Life (HRQOL) Sub-Study will build upon the A2ALL HRQOL measures employed
to date. There is a critical need to look at the important difficulties that liver donors
appear to face not only in the early years but in the long-term after donation. Individuals
who have enrolled in the study and are going to donate a portion of their liver will
complete a HRQOL battery of tests conducted over the phone by experienced staff at
Northwestern University or the University of Pittsburgh. The tests are a series of questions
given to the upcoming donor at baseline (prior to the liver donation), at Month 3, and Month
6, Year 1 and Year 2 following donation. The new donor will complete up to 5 interviews by
the survey research team. Individuals who have already donated (long-term donors), and out
three years since donation can be enrolled, but they have to have donated in 2002 or more
recently. Long-term follow-up donors will complete up to 4 interviews by the survey research
team.

As LDLT moved from children to adults, it was observed early that the size of the graft was
related to function in the recipient and that inadequate graft volume led to poor recipient
outcomes. It has been found, that when the graft of the liver is too small, then the
recipient can develop a number of symptoms including persistent ascites (fluid in the
abdomen) and the graft becomes resistant to the passage of blood. This study hopes to
develop and validate approaches that permit successful use of smaller donor livers and this
is the principal goal of the surgical innovations portion of the study. The study will use
standard surgical technique for the donor and recipient. Either right or left lobe donation
and transplantation will be performed based on clinical parameters for graft selection.

Biosample collection of serum aliquots and liver tissue samples will be collected from
subjects during different timepoints in the study. The collection of patient biosamples and
DNA samples provides a resource with which researchers can rapidly validate clinical
hypotheses and algorithms for clinical decision making. The collections also advance the
development of diagnostic and prognostic markers and therapeutics. In addition, collection
and storage of DNA samples may increase the sample size and the resulting power of a study
to identify genetic determinants of a disease. The samples will be stored in the National
Institute of Diabetic, Digestive and Kidney diseases (NIDDK) Repositories.

Hepatic C virus (HCV) recurrence after liver transplantation is universal in patients who
have the virus pre-operatively. Chronic hepatitis evolves to a cirrhosis at a variable
rate, but more rapidly than in non-transplant patients. The study will evaluate whether
risk factors for aggressive HCV recurrence after DDLT also apply to LDLT recipients in
long-term follow-up.

Pain control in living donors following partial hepatectomy will be measured as quality of
care. The transplant community has no objective information about pain management in live
liver donors to use for quality improvement. A validated tool to measure quality of pain
management will be used to assess multidimensional aspects of pain care.

The following details the schedule of visits and the tests/procedures to be performed at
each visit:

Recipient (before the surgery)

- Provide blood samples for the NIDDK Biosample Repository.

- Undergo imaging studies either Computed Assisted Tomography (CAT) or a Magnetic
Resonance Imaging (MRI) to measure the size of the liver and spleen.

- If one has liver cancer or hepatocellular carcinoma (HCC), information will be
collected about the tumor(s) and treatment.

Recipient (day of surgery)

- Provide a sample of the new liver to the NIDDK Biosample Repository.

- Provide blood samples immediately before the transplant surgery to the NIDDK Biosample
Repository.

- Allow the researchers to collect information about the transplant surgery.

- Allow the researchers to collect information about any complications that develop after
the transplant.

- During the transplant operation, an ultrasound probe will be applied to the two vessels
going to the transplanted liver and a measurement of how much blood flows through these
vessels to the liver will be taken. After less than 5 minutes the probes will be
removed. Additionally, measurements will be taken of the pressure in one of the
vessels, the portal vein, with a very small needle inserted by the surgeon. These
measurements will be recorded and analyzed as part of the study.

- During living donor transplant surgery, it is occasionally necessary to adjust the
blood flow to the liver to improve the function. If the surgeon determines that the
flow to the liver needs to be adjusted, the measurements described above will be
repeated after the adjustments have been made. These measurements will be recorded and
analyzed as part of the study.

- Additional tests which are standard of care may also be carried out at the site.

- If one has HCC,then information will be collected about the tumor(s).

Recipient(immediately after the surgery)

- Provide blood samples during the first and second weeks after the transplant to the
NIDDK Biosample Repository.

- Allow the researchers to collect information about the lab tests (liver function tests,
blood counts,etc.).

- Undergo an ultrasound measurement of the blood flow through the portal vein on the day
after the operation.

- Additional tests which are standard of care may be also carried out at the site.

Recipient (throughout the course of the study)

- Provide blood samples to the NIDDK Biosample Repository at months 1, 3, and 12, and
annually thereafter though August 2014. Approximately 10 teaspoons or 50 ccs of blood
will be collected at each assessment.

- Undergo imaging studies at three months after the operation (either a CAT or MRI) of
the liver and spleen to see how much the liver has grown since the transplant
operation.

- Return to the transplant center for assessment at months 1,3, and 12, and annually
thereafter through August 2014.

- Allow the researchers to collect information about any hospitalizations that occur
after the transplant operation.

- Allow the researchers to collect information about any complications that develop after
the transplant, through August 2014.

- Allow the researchers to collect information about any liver biopsies that are
performed after the transplant.

- If the subject has Hepatitis C (HCV) and is post-transplant, and has had a liver
transplant from a living donor or a deceased donor, the subject will be asked
permission for review of the chart and collect information about the pre-transplant HCV
treatment, the transplant operation, the immunosuppression medications, rejection
episodes, and any HCV treatment received prior to consenting to this study.

- If the subject has HCV,and has given permission, the chart will be reviewed for liver
biopsy results that occurred at least three years after the transplant.

- If a liver biopsy was not done at least three years after the transplant or if the
recent liver biopsy was more than 6 months ago, the subject will be a asked to come to
the center and get a liver biopsy done.

- If the biopsy is done, blood will also be collected and sent for storage to the NIDDK
Repository. Approximately 10 teaspoons or 50ccs of blood will be collected at that
time.

- If a liver biopsy is done, the slides of the liver tissue will be sent to the
central pathologist to read. The name of the subject and any other identifying
information will not be on the slide. It will have a code number on it that links back
to the individuals clinical data.

- If the subject is unwilling or unable to undergo a liver biopsy, then the subject will
be asked to undergo a procedure called "transient elastography". Transient
elastography is a non-invasive procedure during which a sound wave is transmitted to
the liver through an ultrasound probe, and the time it takes for the sound wave to
travel through the liver is measured. Transient elastography is considered to be an
experimental procedure. However, it has been well-studied, and there have been no
adverse events or injuries with its use.

Donor (before the surgery)

- The subject may be called on the telephone by the survey researchers to answer
questions about health, and well-being as well as views about the donation process.

- The survey questions may take up to 45 minutes to complete.

- Provide blood cell samples for the NIDDK Biosample Repository.

- Undergo an imaging study before the operation (either CAT or MRI) to measure the size
of the liver and spleen.

- Additional tests which are standard of care may also be carried out at the site.

Donor (day of the surgery)

- Provide samples of liver to the NIDDK Biosample Repository.

- Allow the researchers to collect information about the donation surgery.

- Allow the researchers to collect information about any complications that develop after
the donation.

Donor (immediately after the surgery)

- Two days after the surgery, the subject will be asked quesitons about their
post-operative pain.

- Provide blood samples one week after the donation surgery to the NIDDK Biosample
Repository. Approximately 5-6 teaspoons or 25-30ccs of blood will be collected.

Donor (throughout the course of the study)

- Provide blood samples to the NIDDK Biosample Repository at week 1, month 1, month 3 and
month 12. Approximately 10 teaspoons or 50 ccs of blood will be collected at each
assessment.

- Return to the transplant center for assessment at month 3, and annually thereafter
through August 2014.

- Undergo an imaging study at three months after the operation (CAT or MRI) to measure
the size of the liver and spleen to see how much the liver has grown back since the
donation operation.

- If the subject entered this study prior to undergoing surgery, questions will have to
be answered by telephone about quality of life after donation at 3, 6, 12, and 24
months following donation. These telephone interviews may take up to 45 minutes to
complete.

- If the subject entered the study after living liver donation, questions will be asked
over the telephone about quality of life upon study entry and then annually for up to
three years. The telephone interviews may take 45 minutes to complete.

- Allow the researchers to collect information about any complications that develop after
the donation operation, through August 2014.

- Allow the researchers to collect information about the hospitalizations that occur
after the transplant operation.