An Early Phase 1 interventional study of Transplantation of Placenta Derived Stem Cells in Diabetic Foot, Diabetic Neuropathies and Diabetic Foot Ulcer, sponsored by Michael H Carstens. Completed at 2 sites in Nicaragua. Open to participants aged 30 Years to 70 Years. Per ClinicalTrials.gov, last updated 2024-04-18.
Sponsored by Michael H Carstens · Early Phase 1, Interventional, and Treatment
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.
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, e.g., 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:
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
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:
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
Study design
Format
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).
617 studies on the registry are indexed under Diabetic Neuropathies; 91 are open to participants now.
This study's enrollment of 20 is below the median of 73 across 510 interventional studies indexed under Diabetic Neuropathies.
Browse Diabetic Neuropathies studies →Michael H Carstens is the lead sponsor of 4 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
The intervention at the foot in group 1 will be carried out by PDSC suspension in 60cc Lactated Ringer's (LR) solution. There will be 3 sequential blocks of subjects with increasing PDSC dose: * Block 1 (4 subjects) Total dosage (30 x 10\*6 cells) * Block 2 (3 subjects) Total dosage (40 x 10\*6 cells) * Block 3 (3 subjects) Total dosage (60 x 10\*6 cells) Administration to the ipsilateral foot / ankle in group 1 is performed by four injection sites: (1) 20 cc into the wound bed, (2) 20 cc subcutaneously around the perimeter of the wound, (3) 10 cc along the tibialis posterior pathway at the ankle prior to entry into the plantar surface, and (4) 10 cc along the tibialis anterior / dorsal foot pathway from the ankle to the dorsum of the foot.
Biological: Transplantation of Placenta Derived Stem Cells
Dosing to the leg in group 2 will be carried out by PDSC suspension of the dose in 90cc LR solution, which will be divided equally among the three compartments of the leg. There will be 3 sequential blocks of subjects with increasing PDSC dose: * Block 1 (4 subjects) Total dosage (30 x 10\*6 cells) * Block 2 (3 subjects) Total dosage (40 x 10\*6 cells) * Block 3 (3 subjects) Total dosage (60 x 10\*6 cells) Administration to the leg will be performed through a 5 mm incision in each compartment (anterior, posterior, and lateral) at a level lower than the anterior tibial tubercle plane. These incisions will allow the introduction of a liposuction cannula of 3-4 mm in diameter and 20 cc in length, with an aroma tip and a single port that will be passed distally until the limit of the compartment is reached and, from there, the PDSCs will be injected retrograde throughout the compartment.
Biological: Transplantation of Placenta Derived Stem Cells
Subcutaneously administered placental-derived SVF / PDSC cells in foot, ankle, and calf tissues in 20 DFU patients
Foot Ulcer Healing
Percent closure based on changes in ulcer size dimensions in square cm.
Time frame: Baseline, 3, 6, 9 and 12 months post treatment.
Fine Touch Sensation: Documenting diabetes-associated lower extremity pathophysiology changes.
Semmes-Weinstein scores to document sensation threshold
Time frame: Baseline, 3, 6, 9 and 12 months post treatment.
Vibration: Documenting diabetes-associated lower extremity pathophysiology changes.
Horwell neurothesiometer scores to document vibration threshold
Time frame: Baseline, 3, 6, 9 and 12 months post treatment.
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Michael H Carstens