Ignite Creation Date:
2024-05-06 @ 2:29 AM
Last Modification Date:
2024-10-26 @ 11:19 AM
Study NCT ID:
NCT02056210
Status:
COMPLETED
Last Update Posted:
2014-10-24
First Post:
2014-02-03
Brief Title:
Stem Cell Mobilization With Plerixafor in Diabetic vs Control Subjects
Sponsor:
University of Padova
Organization:
University of Padova
Study Overview
Official Title:
Mobilization Test of BM Progenitor Cells With Plerixafor AMD3100 Controlled Parallel Group Comparison Between Diabetic and Non Diabetic Subjects
Status:
COMPLETED
Status Verified Date:
2014-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The objective of this study is to assess whether there are differences in the mobilization of CD34 cells and EPC in response to Mozobil in patients with diabetes mellitus compared to subjects without diabetes Currently there are no non-invasive methods for the study of bone marrow function in humans This project aims to evaluate in patients with type 1 or type 2 diabetes mellitus the ability to mobilize CD34 cells and EPC from the bone marrow to the periphery in response to the exogenous mobilizing agent AMD3100 plerixafor Mozobil compared with a group of non-diabetic individuals While it has been recently shown that diabetic patients do not respond to mobilization induced by G-CSF Filgrastim the investigators herein hypothesize that diabetic patients can adequately respond to mobilization induced by Plerixafor
Detailed Description:
Scientific background Diabetes mellitus is associated with an increased prevalence and incidence of cardiovascular diseases It is believed that the high cardiovascular risk in diabetes is attributable to the adverse effects of glucotoxicity and lipotoxicity on endothelial cells Recent data indicate that endothelial repair mechanisms play an important role in determining the integrity of the endothelium and thus the global health of the cardiovascular system Data from our research group demonstrated that the cells involved in endothelial regeneration and neo-angiogenesis including CD34 cells and endothelial progenitor cells EPC are reduced in number and dysfunctional in patients with diabetes mellitus EPC belong to the CD34 cell population and are defined based on the co-expression of endothelial-lineage markers such as VEGF receptor 2 VEGFR2 or KDR These cells are further impaired in diabetic patients with cardiovascular disease It is believed that these changes represent one of the causes of cardiovascular damage in diabetes
The mechanisms underlying the decrease of EPC and other progenitor cells in diabetes are not fully understood Normally EPC reside in the bone marrow and their circulating levels in peripheral blood are very low In response to ischemic injury or vascular damage EPC are mobilized from the bone marrow to peripheral blood Data obtained in experimental models of diabetes mellitus indicate a defect in EPC mobilization from the bone marrow to the peripheral circulation in response to ischemia which results in an impairment of the post-ischemic neo-angiogenetic processes Similar experimental results were obtained by different research groups Our data also show that experimental diabetes reduces the marrow response to exogenous mobilizing agents such as G-CSF and SCF Other clinical data in humans from our and other research groups confirm the hypothesis of a defect in the bone marrow of patients with diabetes mellitus In particular diabetes causes profound alterations of the bone marrow microenvironment associated with microangiopathy and alteration of the stem cells niche These results confirm a study in the mouse model of type 1 diabetes in which it was for the first time identified a specific form of microangiopathy causing depletion of CD34 cells and EPC in the bone marrow
As a consequence of this bone marrow damage our research group has recently shown that the mobilization of CD34 cells and EPC phenotypes is profoundly defective in patients with type 1 and 2 diabetes mellitus
To reach this conclusion the investigators used a test of bone marrow reserve by administering low dose human recombinant G-CSF Filgrastim The study showed that a sub-maximal marrow stimulation is able to highlight differences between diabetics and non-diabetics and is absolutely safe since there have been no significant side effects In a hematology context it was also previously shown that diabetes is a factor predictive of poor mobilization exposing patients to an increased risk of failing stem cell collection for autologous stem cell transplantation
From a functionalmechanistic standpoint it has been demonstrated that an impairment of the CXCL12CXCR4 axis probably contributes to the lack of mobilization of bone marrow stemprogenitor cells associated with diabetes The drug AMD3100 plerixafor Mozobil is a direct antagonist of CXCR4 and inhibits the cellular signal keeping stem progenitor cells within the bone marrow For this reason AMD3100 Plerixafor is rapidly effective for the mobilization of bone marrow stem cells From an experimental point of view it was observed that diabetic animals although not responsive to mobilization induced by ischemia and G-CSF are responsive to mobilization induced by AMD3100 Plerixafor Mozobil is currently approved in Italy for stem cell mobilization in patients with multiple myeloma or lymphoma for the purpose of auto-transplantation in combination with G-CSF in poorly mobilizing patients see SmPC At this stage the effectiveness of Mozobil in inducing mobilization of stem progenitor cells in diabetic patients has not yet been tested
Scientific question The objective of this study is to assess whether there are differences in the mobilization of CD34 cells and EPC in response to Mozobil in patients with diabetes mellitus compared to subjects without diabetes Currently there are no non-invasive methods for the study of bone marrow function in humans This project aims to evaluate in patients with type 1 or type 2 diabetes mellitus the ability to mobilize CD34 cells and EPC from the bone marrow to the periphery in response to the exogenous mobilizing agent AMD3100 plerixafor Mozobil compared with a group of non-diabetic individuals While it has been recently shown that diabetic patients do not respond to mobilization induced by G-CSF Filgrastim the investigators herein hypothesize that diabetic patients can adequately respond to mobilization induced by Plerixafor
Plausibility and clinical relevance It is believed that alterations of stemprogenitor cells secondary to a bone marrow defect contribute to the development of clinical diabetic microangiopathy and macroangiopathy For this reason it is of great interest to explore the mechanisms causing an progenitor cell defects in diabetes and the possible strategies to cope with this A wealth of data coming from animal human and epidemiologic studies indicate that the mobilizing response to G-CSF is impaired in diabetic patients Therefore stem mobilization in diabetes has to be considered an unmet clinical need On the other side preclinical experimental data in animal models of diabetes indicate that AMD3100 Plerixafor is able to mobilize stem and progenitor cells The clinical relevance of the project lies in the possibility to identify a treatment able to restore stemprogenitor cell mobilization in diabetes This can have favorable implications for chronic diabetic complications such as microangiopathy and cardiovascular diseases In fact this project is relevant from a pathophysiological point of view since it is believed that EPC should protect against vascular complications of diabetes Furthermore from a hematologic standpoint being aware that diabetic patients are hyporesponsive to G-CSF whilst responding adequately to Plerixafor would allow to individualize mobilization protocols in view of an autologous hematopoietic stem cell transplantation
Expected adverse events Treatment with Mozobil in combination with G-CSF may be associated with mild adverse events see SmPC Compared to placebo G-CSF the use of Mozobil G-CSF in patients from two clinical trials induced a significantly higher number of grade 1-2 adverse reactions diarrhea 37 vs 17 nausea 34 vs 22 flatulence 7 vs 3 injection site reactions 34 vs 10 dizziness 11 vs 6 No side effects of grade 3-4 were reported
In the present study Mozobil will be given as monotherapy ie not in combination with G-CSF Based on literature data adverse events that may be expected with this type of treatment are mild
In a study of 20 healthy volunteers grade 1 side effects were reported in response to a monotherapy treatment with Mozobil sc cramps or bloating flatulence dry mouth
In a study that involved 10 healthy volunteers treated with Mozobil sc monotherapy the following mild side effects were observed grade 1 erythema or itching at the site of injection headache perioral paresthesia nausea abdominal swelling
A study that involved 25 healthy donors treated with Mozobil sc monotherapy reported the following adverse events of grade 1 mild dizziness nausea flatulence discomfort or feeling of warmth at the injection site perioral paresthesias sweating cephalea
On the basis of these data it can be assumed that the use of Mozobil monotherapy is safe and expected side effects are mild and tolerable for the patient
In addition as with almost all drugs Mozobil can induce allergic reactions and anaphylaxis
The mechanisms underlying the decrease of EPC and other progenitor cells in diabetes are not fully understood Normally EPC reside in the bone marrow and their circulating levels in peripheral blood are very low In response to ischemic injury or vascular damage EPC are mobilized from the bone marrow to peripheral blood Data obtained in experimental models of diabetes mellitus indicate a defect in EPC mobilization from the bone marrow to the peripheral circulation in response to ischemia which results in an impairment of the post-ischemic neo-angiogenetic processes Similar experimental results were obtained by different research groups Our data also show that experimental diabetes reduces the marrow response to exogenous mobilizing agents such as G-CSF and SCF Other clinical data in humans from our and other research groups confirm the hypothesis of a defect in the bone marrow of patients with diabetes mellitus In particular diabetes causes profound alterations of the bone marrow microenvironment associated with microangiopathy and alteration of the stem cells niche These results confirm a study in the mouse model of type 1 diabetes in which it was for the first time identified a specific form of microangiopathy causing depletion of CD34 cells and EPC in the bone marrow
As a consequence of this bone marrow damage our research group has recently shown that the mobilization of CD34 cells and EPC phenotypes is profoundly defective in patients with type 1 and 2 diabetes mellitus
To reach this conclusion the investigators used a test of bone marrow reserve by administering low dose human recombinant G-CSF Filgrastim The study showed that a sub-maximal marrow stimulation is able to highlight differences between diabetics and non-diabetics and is absolutely safe since there have been no significant side effects In a hematology context it was also previously shown that diabetes is a factor predictive of poor mobilization exposing patients to an increased risk of failing stem cell collection for autologous stem cell transplantation
From a functionalmechanistic standpoint it has been demonstrated that an impairment of the CXCL12CXCR4 axis probably contributes to the lack of mobilization of bone marrow stemprogenitor cells associated with diabetes The drug AMD3100 plerixafor Mozobil is a direct antagonist of CXCR4 and inhibits the cellular signal keeping stem progenitor cells within the bone marrow For this reason AMD3100 Plerixafor is rapidly effective for the mobilization of bone marrow stem cells From an experimental point of view it was observed that diabetic animals although not responsive to mobilization induced by ischemia and G-CSF are responsive to mobilization induced by AMD3100 Plerixafor Mozobil is currently approved in Italy for stem cell mobilization in patients with multiple myeloma or lymphoma for the purpose of auto-transplantation in combination with G-CSF in poorly mobilizing patients see SmPC At this stage the effectiveness of Mozobil in inducing mobilization of stem progenitor cells in diabetic patients has not yet been tested
Scientific question The objective of this study is to assess whether there are differences in the mobilization of CD34 cells and EPC in response to Mozobil in patients with diabetes mellitus compared to subjects without diabetes Currently there are no non-invasive methods for the study of bone marrow function in humans This project aims to evaluate in patients with type 1 or type 2 diabetes mellitus the ability to mobilize CD34 cells and EPC from the bone marrow to the periphery in response to the exogenous mobilizing agent AMD3100 plerixafor Mozobil compared with a group of non-diabetic individuals While it has been recently shown that diabetic patients do not respond to mobilization induced by G-CSF Filgrastim the investigators herein hypothesize that diabetic patients can adequately respond to mobilization induced by Plerixafor
Plausibility and clinical relevance It is believed that alterations of stemprogenitor cells secondary to a bone marrow defect contribute to the development of clinical diabetic microangiopathy and macroangiopathy For this reason it is of great interest to explore the mechanisms causing an progenitor cell defects in diabetes and the possible strategies to cope with this A wealth of data coming from animal human and epidemiologic studies indicate that the mobilizing response to G-CSF is impaired in diabetic patients Therefore stem mobilization in diabetes has to be considered an unmet clinical need On the other side preclinical experimental data in animal models of diabetes indicate that AMD3100 Plerixafor is able to mobilize stem and progenitor cells The clinical relevance of the project lies in the possibility to identify a treatment able to restore stemprogenitor cell mobilization in diabetes This can have favorable implications for chronic diabetic complications such as microangiopathy and cardiovascular diseases In fact this project is relevant from a pathophysiological point of view since it is believed that EPC should protect against vascular complications of diabetes Furthermore from a hematologic standpoint being aware that diabetic patients are hyporesponsive to G-CSF whilst responding adequately to Plerixafor would allow to individualize mobilization protocols in view of an autologous hematopoietic stem cell transplantation
Expected adverse events Treatment with Mozobil in combination with G-CSF may be associated with mild adverse events see SmPC Compared to placebo G-CSF the use of Mozobil G-CSF in patients from two clinical trials induced a significantly higher number of grade 1-2 adverse reactions diarrhea 37 vs 17 nausea 34 vs 22 flatulence 7 vs 3 injection site reactions 34 vs 10 dizziness 11 vs 6 No side effects of grade 3-4 were reported
In the present study Mozobil will be given as monotherapy ie not in combination with G-CSF Based on literature data adverse events that may be expected with this type of treatment are mild
In a study of 20 healthy volunteers grade 1 side effects were reported in response to a monotherapy treatment with Mozobil sc cramps or bloating flatulence dry mouth
In a study that involved 10 healthy volunteers treated with Mozobil sc monotherapy the following mild side effects were observed grade 1 erythema or itching at the site of injection headache perioral paresthesia nausea abdominal swelling
A study that involved 25 healthy donors treated with Mozobil sc monotherapy reported the following adverse events of grade 1 mild dizziness nausea flatulence discomfort or feeling of warmth at the injection site perioral paresthesias sweating cephalea
On the basis of these data it can be assumed that the use of Mozobil monotherapy is safe and expected side effects are mild and tolerable for the patient
In addition as with almost all drugs Mozobil can induce allergic reactions and anaphylaxis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None