Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02062944 |
| Other study ID # |
STU00072766 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
March 2013 |
| Est. completion date |
July 2020 |
Study information
| Verified date |
June 2022 |
| Source |
Northwestern University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
The significance of this clinical trial lies in its potential to increase the success of
immunosuppression (IS) therapy withdrawal in liver transplant (LT) recipients, thus
decreasing the negative impact of IS on their long-term outcomes. Lifetime immunosuppression
(IS) with standard agents, the calcineurin inhibitors (CNI) cyclosporine and tacrolimus
(TAC), is currently required at clinically recommended doses and trough levels to prevent
allograft rejection. However, this occurs at the significant expense of long-term CNI
toxicity, i.e. chronic kidney disease (CKD), hypertension, hyperlipidemia, diabetes,
infections and malignancy. With improvements in early graft and patient survival, long term
adverse IS effects have become increasingly important in this rapidly expanding patient
population. The strategies to reduce long term CNI toxicity include dose minimization that
still leaves patients on CNI therapy, conversion to non-CNI therapy, or even complete IS
withdrawal. The second approach, conversion to non-CNI IS therapy, is attractive in the
potential to stabilize or improve renal function and other CNI toxicities. One such
non-nephrotoxic IS agent, the mammalian target of rapamycin inhibitor (mTOR-I) SRL, has a
different mechanism of IS action and studies have shown that CNI to SRL conversion can
stabilize renal dysfunction with a low risk of rejection. Yet even with these possible
benefits, patients on SRL are still subject to lifetime IS therapy with side effects and
costs, highlighting the need to investigate the strategies that promote full IS withdrawal
without rejection (3rd approach), also known as 'operational tolerance'.
Description:
Study Overview The study proposed is a prospective trial of controlled SRL monotherapy
minimization and withdrawal in up to 25 stable non-immune non-viremic LT recipients. Given
the sample size calculations (see Statistical section), we plan to enroll up to 25 SRL
monotherapy patients for this study (Figure 1). All patients will be consented to undergo
laboratory evaluation as well as an enrollment liver biopsy and blood tests. If the patient
meets inclusion/exclusion (I/E) criteria (see below), SRL will be minimized over 6 months
until once a week dosing is achieved. Repeat clinical and immunological blood tests as above
will be performed, and if no biochemical signs of rejection, SRL will be discontinued with
blood tests and liver biopsy 12 months later for similar biochemical, histological and
immunological measures. At any concern for rejection, liver biopsy and assays for equivalent
biochemical, histological and immunological measures will be performed and if rejection is
diagnosed on biopsy, a second attempt at withdrawal will not be performed. Patients will be
monitored as standard of care with clinic visits every 6 months and laboratory tests every 2
weeks. The total study length will be 18 months: 6 month minimization phase and 1 year
follow-up after withdrawal success/failure. The primary outcome will be the proportion of
tolerant patients off SRL therapy with normal liver biochemistry and graft histology at 18
months. Secondary outcomes will include the incidence, severity and reversibility of
rejection, patient/graft survival, resolution of SRL and other non-specific IS effects, and
the assessment of clinical/immunological biomarkers of tolerance. All continuous/categorical
clinical variables will be compared with the appropriate statistical analyses.The goal is
that the primary and secondary aims will provide valuable preliminary data to further
elucidate the mechanisms of mTOR-I immunoregulation and for determining the initial clinical
success/feasibility of the mTOR-I approach (vs. historical 20% CNI withdrawal success seen in
studies from the Immune Tolerance Network [ITN] and other groups). This is all so as to guide
a submission to the Immune Tolerance Network for larger, more adequately powered prospective
trials comparing SRL vs. CNI withdrawal and accompanying biomarker predictors of tolerance.
If this pilot study fails to show a correlation between our biomarkers and the
success/failure of SRL withdrawal, or is associated with an unacceptable low (e.g. <20%) rate
of operational tolerance, then this would avoid the necessity for such large, expensive
trials and support the continued development of alternative approaches to tolerance.
Consent and Initial Phase of Enrollment (see Study Protocol Figure- Appendix A) These liver
transplant candidates (up to 25 SRL) will be approached for consideration and informed
consent into the study. The consent form will include discussion of the risks/benefits of
their current therapy (SRL) and the planned minimization/withdrawal. Specifically, the risks
of minimization/withdrawal (i.e. developing acute or chronic rejection, alloimmune hepatitis
during any portion of the study), although unlikely, will be a major emphasis of the consent
process. The consent form will also include the strict requirement for patients to follow all
instructions from the PI in regard to the close laboratory follow-up occurring throughout the
trial, to diagnose any episode of rejection or concern as early as possible to be able to
respond appropriately. All of the study procedures will be discussed with the patient during
clinic visits. They will be informed that neither participation nor refusal will influence
their clinical care. All laboratory tests or costs related to their care in the study, with
the exception of non-standard of care items (i.e. liver biopsies, blood assays), will be the
responsibility of the patient and/or his/her insurance company. They will be asked questions
afterwards to verify comprehension and then sign the consent form documenting their agreement
to participate. A signed copy of the consent form will be given to them. Participation is
completely voluntary and they may discontinue participation the study at any time without
affecting their care or participation in any other study. No financial compensation will be
given.
Screening Evaluation at Enrollment (see Study Protocol Figure) After long term (> 3 years
post-LT, > 3 months on SRL monotherapy) on SRL monotherapy, inclusion/exclusion criteria will
be reviewed and if appropriate, consent as above will be obtained. If the patient agrees and
signs consent, baseline standard of care screening laboratories complete blood count,
comprehensive metabolic panel, sirolimus (CBC, CMP, SRL trough level, fasting lipid profile,
hemoglobin A1C [HbA1C], urine protein/creatinine ratio) and non-standard of care biomarker
assays (blood immunophenotyping, proteogenomics) and liver biopsy (histology and graft
immunohistochemistry) will be performed as dictated by the protocol. In addition, the liver
biopsy will be used to determine stability in graft function (i.e. no evidence of rejection
or immune-mediated hepatitis) before considering minimization/withdrawal. SRL
minimization/withdrawal will only be performed if clinically, biochemically and
histologically [by biopsy; liver transplant pathology read (Yang, Rao)] stable. Throughout
the entire study, liver function tests will be monitored every 2 weeks (monthly is standard
of care, so the interim non-standard of care 2 week blood tests will be covered by the study
funds). Patients entering the minimization/withdrawal phases will be reduced by a total dose
of 50% of their baseline dose every month until patients are on 0.5 mg SRL daily. At this
point, every other day dosing will begin x 1 month. If no LFT abnormalities, twice weekly
dosing x 1 month, then once a week dosing x 1 month. Prior to complete discontinuation,
repeat clinical (screening labs above) and blood biomarker assays (blood immunophenotyping,
proteogenomics) will be performed. Liver biopsy will not be performed at this juncture unless
there are biochemical signs of liver injury. If complete withdrawal is deemed safe (no
evidence of biochemical abnormalities) patients will be withdrawn completely (i.e. the
once/week SRL dose discontinued) and followed off IS therapy for one year. In this time
period, liver function tests will be monitored every 2 weeks, as usual, and repeat clinical
(screening labs above), liver biopsy and blood (blood immunophenotyping, proteogenomics)
assays performed at the end of this year or at any concern for rejection.
Blood and Tissue Samples Standard of care laboratories (CBC, CMP) will be performed every
month on all patients, and only LFTs performed in the interim 2 weeks between each month
(non-standard of care; covered by the study funds) until complete withdrawal. 3 green top 5
mL and 3 red top 5 mL tubes of blood for biomarker assays will be taken on all patients prior
to study enrollment, prior to complete withdrawal, and one year after withdrawal or at the
time of suspected rejection. Liver biopsy (one 3 cm biopsy- 2 cm for histology and 1 cm for
genomic assays) will be performed at baseline (pre-minimization) and 1 year post withdrawal.
A separate clinical informed consent will be obtained each time a liver biopsy is performed.
If the patient develops elevation in liver transaminases requiring a liver biopsy at any
stage of the study protocol, blood (all for immune monitoring (IM) assays) will be requested
from the patient at the time of the biopsy. If rejection occurs, the patient will be followed
in the study until completion but not be further withdrawn from SRL or have a liver biopsy at
the end of the study
Follow-up Laboratory follow-up is described above- every 2 weeks throughout the trial until
complete withdrawal. Any biochemical (or clinical) signs or significant liver function test
abnormalities will be acted on immediately either by liver biopsy or a pause in IS withdrawal
per investigator discretion. All patients will be seen in the clinic every 3 months to assess
for any new signs or symptoms or resolution of drug side effects in the minimization or
withdrawal arm. Quality of life questionnaires; Post Liver Transplant Quality of Life
Instrument (pLTQ) and the Promis-29 profile v1.0 will be administered at the study onset and
after successful vs. unsuccessful withdrawal (end of study)
Outcome Measures The primary outcome will be the proportion of patients off SRL therapy with
normal liver biochemistry and graft histology at 12 months (i.e. tolerant). Thus, the
incidence of graft dysfunction (acute rejection, immune mediated or autoimmune hepatitis,
chronic rejection) or non-tolerance will be assessed in this SRL withdrawal group and
compared to the historical CNI group (20% tolerant; 80% failure) as the primary endpoint.
This rate will be a composite of the cumulative number of biopsy-proven graft dysfunctions
requiring conversion back to SRL or additional IS therapy or discontinuation of
minimization/withdrawal that occur during the course of the study. Major secondary measures
compared will be the predictive capacity of the blood and graft biomarker assays
(immunophenotyping, genomic/proteomics) before and after minimization/withdrawal in the
success vs. failure groups. Clinical secondary outcomes will be compared: the number of
infectious complications, liver biopsy complications, cardiovascular outcomes (i.e. blood
pressure, diabetes control, lipid levels), renal function, hematopoietic parameters,
gastrointestinal effects, or other side effects of SRL that may or may not improve or develop
with minimization/withdrawal. These will all be documented by a study database during patient
visits, electronic charts and/or by phone communication. Finally, quality of life (Post Liver
Transplant Quality of Life Instrument (pLTQ) and the Promis-29 profile v1.0) will be analyzed
at the end of the study to determine the effect of IS minimization/withdrawal on other health
benefits.
