Ignite Creation Date:
2024-05-06 @ 8:25 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06373809
Status:
COMPLETED
Last Update Posted:
2024-04-18
First Post:
2024-04-08
Brief Title:
Placenta Derived Stem Cells for Treating of Chronic Ulcers and Neuropathy
Sponsor:
Michael H Carstens
Organization:
Michael H Carstens
Study Overview
Official Title:
Diabetic Foot Treatment of Chronic Ulcers and Neuropathy With Transplantation of Placenta Derived Stem Cells PDSC - A Dose Escalation Safety and Exploratory Efficacy Study
Status:
COMPLETED
Status Verified Date:
2024-04
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:
PDSC
Brief Summary:
This is an initial dose escalation safety and exploratory efficacy study to treat two groups of subjects with critically sized diabetic wounds and diabetic neuropathy using placental-derived stem cells PDSC transplanted by injection into soft tissues of the lower limb Its primary objective is safety assessment and its secondary objective is determining optimum PDSC safe dose Group 1 will receive implantation of cells in the ulcer in the ulcer bed and along the distal arterial vessels that supply blood to the foot Group 2 will follow the same protocol for the foot but will have an additional dose of cells implanted in the anterior and posterior compartments of the same leg to determine the impact on peripheral neuropathy Dose escalation and safety will be documented Exploratory measures of efficacy include ulcer healing hemodynamic and anatomical effects on the arteries of the foot and changes in the sensory perceptions of the foot
Detailed Description:
Diabetes mellitus is a global public health threat with a projected global cost of US 825 billion by 2030 and 845 billion by 2045 International Diabetes Federation Angiopathy macrovascular and or microvascular and neuropathy secondary to disease sets the stage for diabetic foot ulceration DFU by initiating cycles of inflammation ulceration infection and hospitalization often resulting in amputation DFU in the context of a combined neuro-ischemic disease has a worse outcome In the United States 54 of all amputations are related to diabetes and in 85 of cases the trigger is a DFU costing 9 to 13 billion per year
Peripheral vascular disease PVD due to arteriosclerosis is also a known cause of ischemic ulcers and is also an aggravating condition of DFU PVD either alone or in combination with diabetes often culminates in amputations and recurrent ulcers that do not heal Approximately 50 of patients with DFU have concurrent vascular disease As surgical revascularization is not always feasible in these patients there is an urgent need to develop alternative therapies capable of improving the blood supply to the ischemic foot
Cell-based therapies have gained attention as viable options to provide the elements necessary to help restore damaged vessels while inducing the formation of new ones Cell products may contain endothelial progenitor cells EPC and or mesenchymal stem stromal cells MSC both critical during vascular repair and formation given the structural involvement of EPC and the documented pro-angiogenic activity of MSC Based on the capabilities of the documented individual cell types for EPC and MSC the use of a combinatorial cell approach in the same product constitutes an interesting alternative for treating vascular disease Multiple small clinical studies have used autologous or allogeneic bone marrow mononuclear cells MNC either directly after bone marrow extraction or after tissue culture to treat critical limb ischemia In general the therapy resulted in an improvement in symptoms such as a decrease in pain and in some studies the ankle arm index and or tissue oxygenation improved
Adipose-derived vascular stromal fraction AD-SVF is a viable option to treat vascular disease given its enrichment in EPC and higher MSC titers compared to other sources eg bone marrow Logistical advantages complement this key multi-phenotypic display as SVF cells can be obtained from same-day processing of easily accessible harvested adipose tissue without the need for a Good Manufacturing Practice GMP processing facility to manufacture an MSC-based product thus making SVF a point of care therapy
It is difficult to treat vascular disease and chronic ulcers caused by PVD and or diabetes in resource-poor countries like Nicaragua Most patients are unable to maintain a limited weight bearing or non-ambulatory state due to the economic imperative of working Patients often have to travel long distances on poor road conditions to obtain medical care Revascularization procedures are not economically possible for the majority of the Nicaraguan population Additionally advanced stem cell procedures that require cell processing facilities pose significant logistical and economic challenges
In such conditions non-healing ischemic wounds present patients and clinicians with undesirable options chronic pain and risk of infection or amputation Given these factors the Nicaraguan Ministry of Health authorized a pilot study in 2014 to evaluate the potential value of freshly isolated autologous adipose-derived SVF cells as an alternative and cost-effective form of treatment for PVD caused by arteriosclerosis and or diabetes
Studies with AD-SVF for vascular insufficiency in Nicaragua
Given the clinical challenge of peripheral vascular disease in Nicaragua the Ministry of Health and Assistance MINSA approved two successive clinical studies to evaluate the safety efficacy and applicability of AD-SVF cells for this indication Both studies were open-label and non-randomized and SVF cells were injected into affected tissues The studies were carried out in the teaching hospitals of the MINSA in León Hospital Escuela Oscar Danilo Rosales Argüello HEODRA in Managua Hospital Escuela Manolo Morales HEMM and in Matagalpa Hospital Escuela Cesar Amador Molina HECAM
Clinical study 1a initial phase Non-reconstructable peripheral vascular disease of the lower extremity in ten patients treated with adipose-derived stromal vascular fraction cells
Clinical study 1b follow-up phase Adipose-derived stromal vascular fraction SVF cells for the treatment of non-rebuildable peripheral vascular disease in patients with critical limb ischemia a 6-year follow-up showing long-lasting results
Clinical study 2 Treatment of chronic diabetic foot ulcers with injections of stromal vascular fraction cells derived from adipose tissue safety and evidence of efficacy at one year
The key lessons learned from the previous studies are as follows
Local administration of SVF cells produces accelerated wound healing
SVF cells are capable of improving arterial blood flow under otherwise ischemic conditions
The administration of SVF along the path of the distal arteries supplying the foot tibialis anterior and tibialis posterior is associated with changes in the waveform and flow velocity compatible with the induction of new vessels and the reduction of distal resistance
Objectives of the study
Primary Objective To determine the safety of transplantation of PDSCs in the lower limb in 20 patients with diabetes and critical size ulcers 10cm2
Exploratory Objective- To determine if PDSC improve diabetes-associated lower extremity pathophysiology
Document wound healing
Quantify flow parameters and elasticity of pedal arteries
Document sensation in the diabetic foot
Study hypotheses
Primary hypothesis - Transplantation of PDSCs in the diabetic foot is safe
Exploratory Hypothesis - PDSC improve diabetes-associated lower extremity pathophysiology
Subcutaneously administered placental-derived SVF PDSC cells in foot ankle and calf tissues as indicated in 20 DFU patients are effective as follows
PDSCs by increasing the distal vessels of the foot can increase the flow rates measured in the tibialis anterior dorsalis of the foot and tibialis posterior
PDSCs when applied near the arteries of the foot affected by diabetes can exert a trophic effect on fibrotic arterial walls
PDSCs by exerting local anti-inflammatory and neo-angiogenesis effects can improve the sensory function of the nerves that serve the foot fibula sural and posterior tibialis
To assess the possible effects on neurological sensation of PDSCs administered subcutaneously in the tissues of the foot ankle and calf as indicated in 10 patients with DFU
PDSCs due to their angiogenic effect can improve increase microcirculation to the peripheral nerves that serve the foot and consequently improve their function
PDSCs due to their antifibrotic effect can reduce perineural fibrosis and consequently improve its function
Study design
Format
Prospective
Open label
Primary Endpoint safety and dose at 3 months 6 months 9 months 1 year
Secondary Endpoint improvements in diabetes associated pathophysiology at 3 months 6 months 9 months 1 year
Intervention PDSC administration to two subject groups - application of PDSCs to the foot with and without to the compartments of the leg
Masking open label
Main objective Safety
Exploratory objective improvement in diabetes associated pathophysiology
Dosage dose escalation
Diagnosis and selection of patients
It is proposed to study 20 patients with a diagnosis of peripheral vascular insufficiency due to diabetes mellitus which manifests as an ulcer for more than 2 months and with vascular anatomy to the point that they are not candidates for surgical intervention
The number of patients in the two groups is based upon a standard approach to dose escalation The study should provide insights into efficacy to be used in subsequent clinical trials but is not powered for an efficacy trial
Study procedures
Processing delivery and storage of PDSC
PDSC will be prepared from the cell bank in Wake Forest Institute for Regenerative Medicine WFIRM as indicated above The technical aspects of the preparation and the associated costs are detailed in Annex 1 Transportation to Nicaragua will be carried out by World Carrier with direct delivery to the National Center for Diagnosis and Reference Centro Nacional de Diagnostico y Referencia CNDR at the Concepción Palacios National Health Complex in Managua
PDSCs will be transported from the -80 freezer in CNDR The freezer is temperature monitored and linked to an active alarm system PDSCs will be transported from the -80 freezer in CNDR to the treatment site on the day of the intervention PDSC will be used within 2 hours of warming Cells not used in a timely fashion will be destroyed and their destruction will be recorded as will the reason that they were not used
Study Structure
Potential subjects will be identified from the León and Matagalpa regions then will be evaluated by the surgical services of the following hospitals 1 Hospital Escuela Oscar Danilo Rosales Arguello León HEODRA 2 Hospital Escuela Cesar Amador Molina Matagalpa HECAM
Peripheral vascular disease PVD due to arteriosclerosis is also a known cause of ischemic ulcers and is also an aggravating condition of DFU PVD either alone or in combination with diabetes often culminates in amputations and recurrent ulcers that do not heal Approximately 50 of patients with DFU have concurrent vascular disease As surgical revascularization is not always feasible in these patients there is an urgent need to develop alternative therapies capable of improving the blood supply to the ischemic foot
Cell-based therapies have gained attention as viable options to provide the elements necessary to help restore damaged vessels while inducing the formation of new ones Cell products may contain endothelial progenitor cells EPC and or mesenchymal stem stromal cells MSC both critical during vascular repair and formation given the structural involvement of EPC and the documented pro-angiogenic activity of MSC Based on the capabilities of the documented individual cell types for EPC and MSC the use of a combinatorial cell approach in the same product constitutes an interesting alternative for treating vascular disease Multiple small clinical studies have used autologous or allogeneic bone marrow mononuclear cells MNC either directly after bone marrow extraction or after tissue culture to treat critical limb ischemia In general the therapy resulted in an improvement in symptoms such as a decrease in pain and in some studies the ankle arm index and or tissue oxygenation improved
Adipose-derived vascular stromal fraction AD-SVF is a viable option to treat vascular disease given its enrichment in EPC and higher MSC titers compared to other sources eg bone marrow Logistical advantages complement this key multi-phenotypic display as SVF cells can be obtained from same-day processing of easily accessible harvested adipose tissue without the need for a Good Manufacturing Practice GMP processing facility to manufacture an MSC-based product thus making SVF a point of care therapy
It is difficult to treat vascular disease and chronic ulcers caused by PVD and or diabetes in resource-poor countries like Nicaragua Most patients are unable to maintain a limited weight bearing or non-ambulatory state due to the economic imperative of working Patients often have to travel long distances on poor road conditions to obtain medical care Revascularization procedures are not economically possible for the majority of the Nicaraguan population Additionally advanced stem cell procedures that require cell processing facilities pose significant logistical and economic challenges
In such conditions non-healing ischemic wounds present patients and clinicians with undesirable options chronic pain and risk of infection or amputation Given these factors the Nicaraguan Ministry of Health authorized a pilot study in 2014 to evaluate the potential value of freshly isolated autologous adipose-derived SVF cells as an alternative and cost-effective form of treatment for PVD caused by arteriosclerosis and or diabetes
Studies with AD-SVF for vascular insufficiency in Nicaragua
Given the clinical challenge of peripheral vascular disease in Nicaragua the Ministry of Health and Assistance MINSA approved two successive clinical studies to evaluate the safety efficacy and applicability of AD-SVF cells for this indication Both studies were open-label and non-randomized and SVF cells were injected into affected tissues The studies were carried out in the teaching hospitals of the MINSA in León Hospital Escuela Oscar Danilo Rosales Argüello HEODRA in Managua Hospital Escuela Manolo Morales HEMM and in Matagalpa Hospital Escuela Cesar Amador Molina HECAM
Clinical study 1a initial phase Non-reconstructable peripheral vascular disease of the lower extremity in ten patients treated with adipose-derived stromal vascular fraction cells
Clinical study 1b follow-up phase Adipose-derived stromal vascular fraction SVF cells for the treatment of non-rebuildable peripheral vascular disease in patients with critical limb ischemia a 6-year follow-up showing long-lasting results
Clinical study 2 Treatment of chronic diabetic foot ulcers with injections of stromal vascular fraction cells derived from adipose tissue safety and evidence of efficacy at one year
The key lessons learned from the previous studies are as follows
Local administration of SVF cells produces accelerated wound healing
SVF cells are capable of improving arterial blood flow under otherwise ischemic conditions
The administration of SVF along the path of the distal arteries supplying the foot tibialis anterior and tibialis posterior is associated with changes in the waveform and flow velocity compatible with the induction of new vessels and the reduction of distal resistance
Objectives of the study
Primary Objective To determine the safety of transplantation of PDSCs in the lower limb in 20 patients with diabetes and critical size ulcers 10cm2
Exploratory Objective- To determine if PDSC improve diabetes-associated lower extremity pathophysiology
Document wound healing
Quantify flow parameters and elasticity of pedal arteries
Document sensation in the diabetic foot
Study hypotheses
Primary hypothesis - Transplantation of PDSCs in the diabetic foot is safe
Exploratory Hypothesis - PDSC improve diabetes-associated lower extremity pathophysiology
Subcutaneously administered placental-derived SVF PDSC cells in foot ankle and calf tissues as indicated in 20 DFU patients are effective as follows
PDSCs by increasing the distal vessels of the foot can increase the flow rates measured in the tibialis anterior dorsalis of the foot and tibialis posterior
PDSCs when applied near the arteries of the foot affected by diabetes can exert a trophic effect on fibrotic arterial walls
PDSCs by exerting local anti-inflammatory and neo-angiogenesis effects can improve the sensory function of the nerves that serve the foot fibula sural and posterior tibialis
To assess the possible effects on neurological sensation of PDSCs administered subcutaneously in the tissues of the foot ankle and calf as indicated in 10 patients with DFU
PDSCs due to their angiogenic effect can improve increase microcirculation to the peripheral nerves that serve the foot and consequently improve their function
PDSCs due to their antifibrotic effect can reduce perineural fibrosis and consequently improve its function
Study design
Format
Prospective
Open label
Primary Endpoint safety and dose at 3 months 6 months 9 months 1 year
Secondary Endpoint improvements in diabetes associated pathophysiology at 3 months 6 months 9 months 1 year
Intervention PDSC administration to two subject groups - application of PDSCs to the foot with and without to the compartments of the leg
Masking open label
Main objective Safety
Exploratory objective improvement in diabetes associated pathophysiology
Dosage dose escalation
Diagnosis and selection of patients
It is proposed to study 20 patients with a diagnosis of peripheral vascular insufficiency due to diabetes mellitus which manifests as an ulcer for more than 2 months and with vascular anatomy to the point that they are not candidates for surgical intervention
The number of patients in the two groups is based upon a standard approach to dose escalation The study should provide insights into efficacy to be used in subsequent clinical trials but is not powered for an efficacy trial
Study procedures
Processing delivery and storage of PDSC
PDSC will be prepared from the cell bank in Wake Forest Institute for Regenerative Medicine WFIRM as indicated above The technical aspects of the preparation and the associated costs are detailed in Annex 1 Transportation to Nicaragua will be carried out by World Carrier with direct delivery to the National Center for Diagnosis and Reference Centro Nacional de Diagnostico y Referencia CNDR at the Concepción Palacios National Health Complex in Managua
PDSCs will be transported from the -80 freezer in CNDR The freezer is temperature monitored and linked to an active alarm system PDSCs will be transported from the -80 freezer in CNDR to the treatment site on the day of the intervention PDSC will be used within 2 hours of warming Cells not used in a timely fashion will be destroyed and their destruction will be recorded as will the reason that they were not used
Study Structure
Potential subjects will be identified from the León and Matagalpa regions then will be evaluated by the surgical services of the following hospitals 1 Hospital Escuela Oscar Danilo Rosales Arguello León HEODRA 2 Hospital Escuela Cesar Amador Molina Matagalpa HECAM
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None