Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04198350 |
| Other study ID # |
19SM5165 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2022 |
| Est. completion date |
March 2023 |
Study information
| Verified date |
February 2023 |
| Source |
Imperial College London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is a phase II prospective, interventional, open-labeled, proof-of-concept study.
2 years per participant, 2 years 6 months in total Total n=6
The primary objective is to assess the safety of human pancreatic islet transplantation into
the ACE of participants with T1D.
Safety analyses will involve examination of the incidence, severity, and type of treatment
emergent AEs reported, and changes in vital signs, ophthalmic status and laboratory test
results from baseline (Day 0 pre-transplantation) to specified time points throughout the
study.
Description:
Type 1 diabetes (T1D) is caused by the destruction of pancreatic islet cells through an
autoimmune attack against insulin-producing beta cells in the endocrine pancreas. This in
turn impairs glucose control causing multi-organ failure, morbidity and mortality which are
also associated with high economic costs. While strict glucose control with insulin
replacement therapy is the standard-of-care, achieving controlled glucose homeostasis remains
a major challenge. Replacement of the insulin-producing beta cells through pancreatic islet
transplantation has emerged as a promising therapy for T1D. Thus far, hundreds of islet
transplantations have been performed in ongoing clinical trials worldwide. Islet
transplantation is on the verge of obtaining FDA approval as a standard therapy in T1D. While
ongoing clinical trials have focused on islet transplantation into the hepatic portal system,
the search for alternative islet transplantation sites remains a priority for funding
agencies and an active area of research. Studies have explored islet transplantation into
different locations. One location of interest is the anterior chamber of the eye (ACE).
Importantly, these studies have shown several advantages offered by islet transplantation
into the anterior chamber of the eye compared to other sites, which include:
- Local/topical immunosuppression and intervention potentially feasible.
- No IBMIR (Instant Blood Mediated Inflammatory Reaction) as when islets are injected to
the portal vein with a major loss of islets.
- Good survival of transplanted islets due to limited anoxia time (fewer islets required
to improve glycaemic control compared to other islet transplantation sites (i.e.,
liver)).
- Non-invasive monitoring/assessment of grafted islets with potential cellular resolution.
- Intraocular islets may function as "reporters" of native islets or islets transplanted
elsewhere.
- Simpler surgical procedure as compared to other islet transplantation sites (i.e.,
liver).
Access to the ACE is a safe procedure routinely used by ophthalmic surgeons for the anterior
segment surgery (e.g. cataract operations) and extraction of intraocular fluid for diagnostic
purposes. Importantly, the ACE has unique immunological properties which regulate the immune
system in such a way that allogeneic tissue placed in this compartment may be protected from
immune rejection and this correlates with the generation of systemic immune tolerance through
anterior chamber-associated immune deviation (ACAID) (Niederkorn and Streilein, 1982;
Streilein and Niederkorn, 1985). Hence, the potential of inducing systemic immune tolerance
and eliminating severe side-effects associated with systemic immunosuppression through
local/topical drug application further highlight the significance and clinical relevance of
this approach. Moreover, this introduces the possibility of transplanting additional islets
elsewhere in the body without risk of rejection. Importantly, it was recently shown that
islet grafts in the ACE also serve as "reporters" for the status of the pancreatic islets
(Ilegems et al., 2013). This essentially demonstrates that islets in the ACE are reliable,
easily accessible reporters for the overall health and islet function during interventions
regimens aimed at regulating different aspects of the pancreatic islets.
INTERVENTION AND INDICATION
We intend to transplant six T1D participants with reduced vision in one or both eyes due to
diabetes or other complications. Transplantation of allogeneic pancreatic human islets will
be performed into the anterior chamber of a single eye with the poorest visual acuity (see
inclusion/exclusion criteria below). Up to 40 000 IEQ of islets in a maximum volume of 350µl
will be transplanted.
RATIONALE FOR THE INTENDED INTERVENTION
Improvement in glycaemic control is expected with the intended intervention, as measured with
change in C-peptide, insulin, proinsulin and glucose levels during the MMTT, change in
insulin requirements, change in HbA1c levels and in fasting glucose from baseline, change in
total number of hypoglycaemic events, change of hypoglycaemia awareness, change in glycaemia
fluctuations after transplant at Day 90, 180 and 365 post-operatively.
RISKS / BENEFITS
Successful islet transplantation reduces the risk to people with T1D of life-threatening
hypoglycaemia and psychosocially debilitating glycaemic lability. While the long-term
durability of these responses is at present uncertain, they persist for as long as some graft
function is maintained, despite the eventual return to insulin therapy in the majority of
islet transplant recipients in clinical trials of islet transplant in other sites. This
partial function, as indicated by continued c-peptide production, may be present in as many
as 80% of recipients after 5 years. Given our preliminary studies, however, a "marginal"
islet mass in the anterior chamber of the eye may prove superior in conveying better
function. Nonetheless, as long as graft function is maintained, fear of hypoglycaemia and
anxiety are significantly lower after islet transplantation. Indeed, T1D participants with
persistent c-peptide production have a significantly reduced risk of severe hypoglycaemia.
Additionally, while most transplant recipients experience only a temporary reprieve from
exogenous insulin therapy, a few have maintained insulin-independent graft function for more
than 3 years. Shorter engraftment period in the anterior chamber of the eye may promote
better survival of transplanted islets and lead to improved long-term graft function and
further the duration of insulin-independence after transplantation, potentially leading to
reductions in the secondary complications of T1D. At present, systemic immunosuppression is
needed in all types of allogeneic organ- or cell transplantations. Due to the well-known side
effects and risks involved with this medication the benefit from the procedure must out-weigh
the risks. The benefit from the proposed treatment is unknown and therefore we have chosen
participants that are already treated with immunosuppression not to lay this additional
burden upon them.
Ophthalmic complications may include: elevated intraocular pressure, infection, corneal
edema, severe inflammation, progression of diabetic retinopathy, or anterior segment
neovascularization.
Only people with reduced VA in the treated eye and equal or better VA in the fellow eye will
be included. Systemic complications due to the intervention are not expected. Nevertheless,
systemic effects will be carefully monitored including possible immunization against the
donor cells.
The proposed pilot study will mainly focus on the safety of islet transplantation to the ACE
in a narrowly selected group of participants. However, if the study is successful we intend
to treat participants with less severe disease and with broader systemic inclusion criteria.
Ultimately, islet transplantation to the ACE may become an alternative route for cell therapy
and disease monitoring in insulin-treated diabetes.
The islets will be transplanted into the eye with reduced vision to minimise any side-effects
affecting your vision. The primary aim of the study is to evaulaute safety of the
transplanting islets in the eye and regular eye examinations will be carried out throughout
the study to identify any potential potential post-surgical risks caused by the transplanted
islets which may include increased pressure in the eye, infection, swelling of the cornea,
severe inflammation, progression of pre-existing diabetic retinopathy, or the formation of
new blood vessels in the eye. To prevent these complications eye drops and antibiotics will
be given. If needed a steroid injection can be administered to help with any issues and if
necessary the transplanted islets will be removed.
JUSTIFICATION OF CHOICE OF STUDY POPULATION
Six people with T1D with reduced vision in one or both eyes due to diabetes or other
complications, will be included in the study. Within this population we expect to identify
participants with preserved anterior segment integrity which in turn reduces the risk of
treatment-related complication. The choice of T1D participants facilitates evaluation of
change in C-peptide and insulin levels. Islets may be surgically removed if uncontrolled
complications cannot be managed non-surgically.
HYPOTHESIS
In this study, we aim to demonstrate safety and feasibility of pancreatic islet cell
transplantation in the human eye. Also, its efficacy in restoring/improving glycaemic control
should be demonstrated.
