Autologous Adult Stem Cells to Patients With Type 1 Diabetes and a Successful Renal Transplant

Study Overview
=================
Brief Summary
-----------------
This is a phase I study to assess the safety and tolerability of infusing expanded stem cells into the pancreas of patients with type I diabetes and a successful renal transplant. The stem cells used in this study occur naturally in the body and are collected from each recipient by a procedure called leukapheresis. The cells are then expanded and differentiated into insulin-like cells in a sterile suite before being injected into the body or tail of the pancreas of the recipient.

Detailed Description
-----------------
Islet transplantation as a potential treatment for diabetes has been investigated extensively over the past 10 years. Such an approach, however, will always be limited mainly because it is difficult to obtain sufficiently large numbers of purified islets from cadaveric donors. One alternative to organ or tissue transplantation is to use a renewable source of cells. Adult stem cells are clonogenic cells capable of both self-renewal and multilineage differentiation. These cells have the potential to proliferate and differentiate into any type of cell and to be genetically modified in vitro, thus providing cells, which can be isolated and used for transplantation. Recent studies have given well-defined differentiation protocols, which can be used to guide stem cells into specific cell lineages as neurons, cardiomyocytes and insulin-secreting cells. Moreover, these derived cells have been useful in different animal models. In this regard, insulin-secreting cells derived from R1 mouse embryonic stem cells restore blood glucose concentrations to normal when they are transplanted into streptozotocin-induced diabetic animals. Our group has isolated stem cells (Cluster Designated (CD) 34 positive subset of stem cells) that are capable of differentiating into multiple tissue types ex vivo. In defined conditions, in culture, about 40 percent of the cells produce insulin and reduce blood sugar levels in streptozotocin-induced mice. Clinically, we have performed a phase I trial of stem cell administration to patients with liver insufficiency. The procedure was well tolerated with no specific side effects and with sustained signs of clinical benefit. These results support this protocol for the application of adult stem cell therapy in the treatment of diabetes. In order to evaluate potential clinical applications for these recent advances we have designed a prospective Phase I clinical study of the expanded progeny of an adult CD34 positive subset (InsulinCytes) injected directly into the body and tail of the pancreas of the participants via selective catheterisation of the splenic artery. The study group consists of patients with complicated diabetes mellitus type I plus kidney transplantation with the aim of ascertaining whether this confers clinical benefit as a treatment model for diabetes. Granulocyte colony-stimulating factor (G-CSF) will be administered to suitable patients to mobilise their haematopoietic stem cells (HSCs) from the bone marrow into the peripheral circulation. These blood cells will be collected from each patient by leukapheresis. CD34 positive stem cells will then be isolated by immunoselection and introduced into a Nunc cell factory where the subset of CD34 positive stem cells will be allowed to attach to the plastic trays within the cell factory for 2 hours at 37 degrees C in 5 percent carbon dioxide. After this period the non-attached CD34 positive cells will be washed from the system and the progeny of the attached cells secreted into the supernatant media expanded in the presence of growth medium supplemented with growth factors. At the end of 6 days expansion, the stem cells will be differentiated into insulin and c-peptide protein excreting cells over the next 14 days by the addition of specified reagents/growth factors and continued incubation at 37 degrees C in 5 percent carbon dioxide in accordance with the principles of Good Manufacturing Practice (GMP). As an optional step the cells can be labelled with iron oxide to allow tracking of the cells by Magnetic Resonance Imaging (MRI) scan, before being infused into the patient. An ongoing institute experience with liver failure patients who have been infused with undifferentiated stem cells has shown that an administered dose of up to 2 x 10 log 9 cells was well tolerated. The proposed study group will consist of 10 Type I or Type 2 diabetic patients who have had a successful previous kidney transplant. The primary purpose of the study is to assess the safety and tolerance of stem cell infusion into the pancreas and then to assess the impact of this new modality in the treatment of diabetes.

Official Title
-----------------
A Phase I Safety and Tolerability Study Following the Infusion of Autologous Expanded Progeny of an Adult CD34+ Stem Cell Subset (InsulinCytes) to Patients With Type I Diabetes Mellitus and a Successful Renal Transplant

Conditions
-----------------
Type 1 Diabetes, Type 2 Diabetes

Intervention / Treatment
-----------------
* Biological: Autologous CD34+ stem cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female patients aged from 16 to 65 years of age Patient with Type I or Type 2 diabetes mellitus plus: Successful previous kidney transplant. Good kidney allograft function /no episodes of rejection for at least one year post-transplant Not taking steroids as part of standard immuno-suppression Has a WHO performance score of less than 2 Has a life expectancy of at least 3 months Ability to give written consent Women of childbearing potential may be included, but must use a reliable and appropriate contraceptive method Exclusion Criteria: Patients below the age of 16 or above the age of 65 years Patients with chronic pancreatitis and poor exocrine pancreatic function Pregnant or lactating women Patients with recent recurrent GI bleeding or spontaneous bacterial peritonitis Patients with evidence of HIV or other life threatening infection Patients unable to give written consent Patients with a history of hypersensitivity to G-CSF Patients who have been included in any other clinical trial within the previous month

Ages Eligible for Study
-----------------
Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Autologous stem cells
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous CD34+ stem cells<br>Up to 5 x 10 log 8 of autologous stem cells on a single occasion | Biological: Autologous CD34+ stem cells<br>* Up to 5 x 10 log 8 of autologous stem cells on a single occasion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Adverse Events | Safety will be evaluated in terms of adverse events graded according to CTCTAE toxicity criteria and laboratory test results. All adverse events will also be graded for relationship to treatment and as expected and unexpected. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hba1C Data of Pre and Post Stem Cell Infusion | Mean HbA1c laboratory measurements pre and post stem cell infusion | 12 weeks | 
| Insulin Level | Mean insulin requirement was calculated for each participant pre and post stem cell infusion | 12 weeks | 
| Amylase Level | Each participant had mean amylase data analysed to give a pre and post mean result | 12 weeks | 
| Serum Creatinine | Each participant had serum creatinine analysis pre and post stem cell infusion to give mean result | 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
diabetes type I, diabetes type 2, renal transplant, stem cells, successful renal transplant