Islet Transplantation Clinical Trial
Official title:
A Randomized Controlled Trial to Determine if Sitagliptin Will Enhance Islet Graft Function When Given for 1 Year Following Transplantation
Islet transplantation requires a large number of islets required to achieve insulin independence and the function of the transplanted islets progressively declines over time. Evidence from animal studies and human islets in culture suggests that increasing GLP-1 levels could help with both of these problems. This study is designed to test this hypothesis using sitagliptin in a randomized clinical trial.
Hypothesis: Sitagliptin taken for 12 months after an islet infusion will significantly
improve islet function compared with a control group.
Purpose: To determine if sitagliptin given at the time of an islet cell transplant (ICT)
results in improved islet graft function at 3 and 12 months post-transplant.
Study design: prospective, randomized, double-blind, single-centre, placebo-controlled trial.
Sample size calculation for primary outcome.
The primary outcome (stimulated insulin secretion) is a continuous variable that is normally
distributed. Our previous clamp studies show an expected standard deviation of around 20% and
we wish to be able to detect an increase of 33%. The result will be calculated both with and
without adjustment for the number of IE / kg that a patient has received, since the
literature is not clear on this issue. Analysis will be done using a two-sided t test. Sample
size is estimated using an approximation of Lehr's formula for 80% power and 2-sided
significance level of 5%.
m = 16 where d = δ δ = 33%, σ = 20% d 2 σ The calculation indicates a need for 6 patients per
arm or a total of 12 patients for the 2 arms.
Ability of our site to perform the study
Since starting in 2003, we have performed 75 islet infusions in 31 patients, averaging one
infusion per month. We are 1 of the 4 most active sites in North America (Edmonton, Miami,
Minnesota are the others). We have a list of patients activated and waiting for a suitable
islet donor. We anticipate that the great majority of patients will choose to participate in
this trial. We should easily be able to perform the required 12 islet infusions within 2
years. The advantage of performing this study in a single therapy is the ability to keep
constant variables such as eligibility criteria for recipients and choice of
immunosuppressive drugs that differ considerably between centres. This approach increases the
chances that the question posed will be answered by the study.
Eligible patients Eligible patients will be those in our transplant program who are about to
undergo an infusion of donor islets. Criteria for entry into our program are as described
(Warnock et al Arch Surg 2005;140:735). All eligible patients will be offered a chance to
enter the study. Patients will need to sign an informed consent that has been approved by the
Clinical Research Ethics Board of the University of British Columbia.
Randomization and Blinding Random numbers will be computer generated and placed in opaque
sealed, numbered envelopes. The ratio of sitagliptin and placebo will be 1:1. The pharmacist
associated with the islet transplant team will be the only team member with knowledge of the
code for sitagliptin and placebo. Randomization will be done in blocks of four. The advantage
of block randomization is to allow similar distribution among groups of any changes in
performance of islet transplantation, such as new immunosuppression regimens, that could
arise during the course of the study. There will not be any stratification. Randomization
will be done just prior to islet infusion so that patients receiving either placebo or
sitagliptin will be given their medication before receiving islets.
The subject and the investigators obtaining consent, performing the transplant, providing
post-transplant care and performing the hyperglycemic clamp will be blind as to whether a
subject is receiving sitagliptin or placebo. The placebo will be supplied by Merck and will
be identical in appearance to sitagliptin. Sitagliptin and the placebo will be stored in the
VGH pharmacy.
When a subject consents to participate in the study, the investigator obtaining the consent
will contact the pharmacy. The pharmacy will open the next randomization envelope and
dispense the medication (sitagliptin or placebo). Ongoing supply of the medication will be
provided by the pharmacy in the transplant clinic during routine follow-up visits for
post-transplant care.
Patient Care
All aspects of the transplantation procedure, immunosuppressive therapy and ancillary care
will be performed as described (Warnock et al Arch Surg 2005;140:735) and will be similar for
all patients for the duration of the study. The indications for stopping or restarting
insulin are those recommended by the metabolic monitoring committee of the Collaborative
Islet Transplant Registry. This will eliminate subjective investigator judgments that could
affect one of the secondary endpoints (insulin dose).
Assessment of endpoints
Primary: Maximum insulin secretory capacity will be determined by a hyperglycemic glucose
clamp, performed as described (Al Ghofaili et al Transplantation 2007;83:24). This will be
performed at 3 and 12 months ± 2 weeks after islet infusion, with the subject having received
either sitagliptin or placebo during this period. The medication will be stopped for 48 hours
before the clamp to allow washout. A positive result would suggest that sitagliptin had
increased functional islet mass, not that it was acting as a short-term secretagogue. The
values will be expressed both as absolute numbers and as divided by the number of IE / kg
received as it is not clear from the literature which is the better measurement. A baseline
fasting C peptide will be drawn prior to the islet infusion.
Secondary: Patients are followed closely post transplant to maintain tight glucose control.
Insulin adjustment and glucose targets are as described. The average daily insulin
requirement in the week before transplant and in the week prior to stopping the study will be
used for calculation. A positive result would be consistent with either an increase in
functional islet mass or stimulation or insulin secretion.
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