Kidney Failure, Chronic Clinical Trial
Official title:
The Highly Sensitized Patients: Effects of Mycophenolate Mofetil (MMF) On Anti-Human Leukocyte Antigen (HLA) Antibody Levels In Patients Awaiting Cadaveric Renal Transplant
This is a 12-month, phase II, prospective, open label study, to evaluate the effect of
mycophenolate mofetil (MMF) among patients on the kidney transplant list with high Panel of
Reactive Antibody (PRA) levels.
On average, increasing the PRA from 0 to 50% specifically in the Washington Organ
Procurement Organization (OPO) increases the waiting time from 3 to 6 years. Spontaneous
decreases in the PRA rarely occur and is associated with a decreased chance for
transplantation and a decreased rate of survival.
HYPOTHESIS: mycophenolate mofetil given over 8 months to highly sensitized subjects awaiting
kidney transplant, will result in a decrement in the PRA by 10% or more in approximately 40%
of patients. This decrement should allow an improved rate of transplantation.
BACKGROUND: Patients who have been exposed to human tissue by prior transplants, blood
transfusion or pregnancy may develop anti-bodies against the 'cell markers of human white
blood cells' called 'Human Leukocyte Antigens' (HLA). Preformed anti-bodies to these foreign
human tissues is called SENSITIZATION. Sensitized patients are more likely to reject a
kidney from a donor who possesses the antigenic profile to which they are already
sensitized. This limits the recipient's possible donor pool out of the general population.
The Panel of Reactive Antibodies (PRA) is a test panel that represents the HLA antigenic
profile of the local community. The test panel is used to measure the recipient's reactivity
(by percent) to a variety of HLA antigens. A PRA of 75% means the patient reacted to 75% of
the antigens on the test panel. A PRA panel greater than 50% indicates that the subject
(potential organ recipient) already has a significant number of antibodies pre-formed to
other human tissue and is highly sensitized. Spontaneous decreases in PRA titers rarely
occur thus the probability of transplantation in sensitized patients is significantly
decreased.
STUDY POPULATION: adult University of Washington Medical Center patients, on the kidney
transplant waiting list who are currently receiving dialysis with a PRA level over 50% and
for a period of 6 months or longer.
TREATMENT PLAN/ INTERVENTION:
CONSENT: Consent will be obtained from all subjects. SCREENING: Prior to starting MMF, a
thorough medical history physical exam will be obtained. Patients will be screened
clinically for occurrence of infection and for protective antibodies in response to prior
vaccinations and assure that they are up to date with their immunizations.
INVESTIGATIONAL PRODUCT: Mycophenolate mofetil (MMF) is used as a routine therapy for the
prevention of rejection in transplant recipients and is also used routinely for the
treatment of autoimmune disease and primary renal diseases such as IgA nephropathy and lupus
nephritis.
HOFFMANN LA ROCHE: Will provide Mycophenolate mofetil, MMF as CellCept well as costs for
laboratory testing.
DOSAGE AND ADMINISTRATION: MMF will be dispensed by investigational drug pharmacists in
250mg capsules, taken orally twice daily. Dosing of MMF will begin at 500 mg bid for 30 days
then increased to 1 gm bid if subject is not experiencing undo gastrointestinal side effects
or a decrease in WBC.
STUDY DESIGN:
The subjects will be continually evaluated for 12 months. Month 4: If the subject's PRA
drops by 10% at month 4, subject will remain on MMF without any changes. If subject's PRA
does NOT drop by 10% at month four and infections have NOT occurred, subject will remain on
MMF and increase dosage if possible.
If at month four, more than 4 serious infections have occurred the MMF dose will be reduced
and or stopped for that subject. If stopped they will be followed for 4 months.
Month 8:
If the subject's PRA does NOT drop by 10% at month 8, the MMF will be discontinued and the
subject will be followed for the next 4 months to month 12 post enrollment.
If subject's PRA DOES drop by 10% at month 8 and NO infection(s) have occurred, subject will
continue on MMF to month 12. Study subjects will be followed for a maximum of 12 months.
OBJECTIVES:
The primary endpoint:
1) The number of subjects who achieve a PRA reduction of 10% or greater within 8 months of
initiating mycophenolate mofetil (MMF)therapy.
The secondary outcome measures will include:
1. The number of subjects who received a transplant during the study,
2. The number of subjects who experienced Institutional Review Board (IRB) reportable
infections,
3. The number of subjects who's white blood cell count (WBC) or Immunoglobulin G or M
(IgG/ IgM) titers are below range,
4. The number of transplants with a negative crossmatch.
CLINICAL AND LABORATORY EVALUATIONS:
LAB ASSESSMENT:
Immunology: PRA (panel of reactive antibodies) will be taken monthly and the levels of
individual HLA anti-bodies will be evaluated every other month.
Safety:
Total levels of Immunoglobulin G (IgG) and Immunoglobulin M (IgM), as measures of the
indigenous anti-body population levels. As well as HepB surface Antibody and CMV are tests
done to monitor to screen for changes in the health of the subject's immune system ie. loss
of memory for immunization.
A complete blood count (CBC) is taken at each visit to screen for anemia. Differential
analysis on CBD for screening against platelet reduction and possible bone marrow
suppression. The subject's CBC will be checked more frequently if his/her WBC, hematocrit or
platelets are low. Subjects will be followed closely through 12 months.
;
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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