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The purpose of this study is to determine the safety and efficacy of intraarticular injection of Cell-free Stem Cell-derived Extract Formulation for treatment of knee osteoarthritis symptoms.
Osteoarthritis and other orthopaedic acute and degenerative conditions affect millions of people each year, resulting in significant pain and disability. Conservative modalities are limited, as they may not reverse the underlying pathology and may only provide minimal relief.
To address the limitations of traditional conservative modalities, there has been substantial interest in biologics for musculoskeletal regenerative medicine applications. The efficacy of these biologics is attributed to the presence of stem cells, growth factors (GFs), cytokines (CKs), and extracellular vesicles (EVs) including exosomes.
However, first generation biologics, specifically whole stem cell products, are not without their own inherent limitations, including establishing a reliable source with a stable phenotype, genetic instability and chromosomal aberrations, intravenous administration related toxicities caused by the physical trapping of the cells in the lung microvasculature, rejection by the host, formation of ectopic tissue, and tumorigenicity.
When considering how to harness the value of current biologics into a next generation product that can address existing limitations, it is important to consider current foundational knowledge regarding the mechanism of action of stem cell products. Recent literature regarding the beneficial effects of mesenchymal stem cells (MSCs) postulates that the mechanism of action is not due to their ability to grow and differentiate. Rather, it is secondary to their secretion of bioactive molecules such as growth factors, cytokines, and exosomes. GFs, secreted from stem cells, induce signal transduction pathways that initiate cell migration, proliferation, growth, and differentiation. CKs, similarly, can regulate inflammation, immune response, cellular differentiation, and tissue remodeling. Exosomes also are secreted by mesenchymal stem cells and act as a paracrine mediator to target cells, providing a regenerative microenvironment for damaged tissues.
As existing literature establishes that these aforementioned components of stem cells lead to regenerative responses, we have accordingly sought to establish if a sub-cellular approach to biologics can provide similar benefits while avoiding the risk profile, including immunogenicity, infection, and the potential for tumorgenicity, associated with whole stem cell products. In support of this hypothesis, recent studies have demonstrated that MSCs-derived exosomes can act as a cell-free therapeutic alternative to whole cell therapy with great regenerative potential. In addition, to the benefits by means of risk elimination, there may be further therapeutic benefits of a cellular derived therapeutic approach. For example, exosomes due to their smaller size, have the potential to migrate to target organs efficiently after, without getting trapped in the lung microvasculature. Additionally, a higher concentration of "active ingredients" can be administered directly to the patient, which may induce a larger healing response than is possible with whole stem cell therapies.
To meet these goals of improving the risk profile and therapeutic benefit of regenerative medicine, we have formulated a novel cell-free stem cell-derived extract, CCM, from human progenitor endothelial stem cells (hPESCs). Our preliminary results demonstrated presence of several GFs, anti-inflammatory CKs and EVs including exosomes in this formulation. Functionally, this formulation also significantly enhanced cell proliferation and induced stem cell migration.
The goal of this proposed study is to evaluate the safety and efficacy of intraarticular injection of this cell-free stem cell-derived extract formulation for treatment of knee osteoarthritis symptoms. We hypothesize that intraarticular administration of this cell-free stem cell-derived extract formulation is safe. We also hypothesize that patients receiving intraarticular injection of this formulation will show an improvement in their overall satisfaction, Numeric Pain rating Scale (NPRS), Patient-Reported Outcomes Measurement Information System (PROMIS) score and Knee Injury and Osteoarthritis Outcome Score (KOOS Jr.) over a period of 2-years compared to the baseline visit. Our null hypothesis is that there is no difference between baseline and follow-up visits for any outcome measures.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cell-free Stem cell-derived Extract Formulation (CCM) | Experimental | Intraarticular administration of CCM |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Cell-free Stem Cell-derived Extract Formulation (CCM) | Biological | Intraarticular injection |
|
| Measure | Description | Time Frame |
|---|---|---|
| Treatment-emergent adverse effects as assessed by Comprehensive Metabolic Profile | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Comprehensive metabolic profile | 1 week |
| Treatment-emergent adverse effects as assessed by Comprehensive Metabolic Profile | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Comprehensive metabolic profile | 6 weeks |
| Treatment-emergent adverse effects as assessed by Comprehensive Metabolic Profile | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Comprehensive metabolic profile | 3 Months |
| Treatment-emergent adverse effects as assessed by Comprehensive Metabolic Profile | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Comprehensive metabolic profile | 6 Months |
| Treatment-emergent adverse effects as assessed by Comprehensive Metabolic Profile | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Comprehensive metabolic profile | 12 Months |
| Treatment-emergent adverse effects as assessed by Creatinine levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Creatinine levels | 1 Week |
| Measure | Description | Time Frame |
|---|---|---|
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to immediately after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Craig Cady, PhD | Contact | 2174161497 | cjcady@icloud.com |
| Name | Affiliation | Role |
|---|---|---|
| Craig Cady, PhD | General Therapeutics | Study Director |
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| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34416898 | Derived | Gupta A, Maffulli N, Rodriguez HC, Mistovich RJ, Delfino K, Cady C, Fauser AM, Cundiff ED, Martinez MA, Potty AG. Cell-free stem cell-derived extract formulation for treatment of knee osteoarthritis: study protocol for a preliminary non-randomized, open-label, multi-center feasibility and safety study. J Orthop Surg Res. 2021 Aug 20;16(1):514. doi: 10.1186/s13018-021-02672-3. |
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| ID | Term |
|---|---|
| D020370 | Osteoarthritis, Knee |
| ID | Term |
|---|---|
| D010003 | Osteoarthritis |
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
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| Treatment-emergent adverse effects as assessed by Creatinine levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Creatinine levels | 6 Weeks |
| Treatment-emergent adverse effects as assessed by Creatinine levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Creatinine levels | 3 Months |
| Treatment-emergent adverse effects as assessed by Creatinine levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Creatinine levels | 6 Months |
| Treatment-emergent adverse effects as assessed by Creatinine levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Creatinine levels | 12 Months |
| Treatment-emergent adverse effects as assessed by Liver Function Test | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Liver Function Test | 1 Week |
| Treatment-emergent adverse effects as assessed by Liver Function Test | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Liver Function Test | 6 Weeks |
| Treatment-emergent adverse effects as assessed by Liver Function Test | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Liver Function Test | 3 Months |
| Treatment-emergent adverse effects as assessed by Liver Function Test | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Liver Function Test | 6 Months |
| Treatment-emergent adverse effects as assessed by Liver Function Test | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Liver Function Test | 12 Months |
| Treatment-emergent adverse effects as assessed by Complete Blood Count | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Complete Blood Count | 1 Week |
| Treatment-emergent adverse effects as assessed by Complete Blood Count | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Complete Blood Count | 6 Weeks |
| Treatment-emergent adverse effects as assessed by Complete Blood Count | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Complete Blood Count | 3 Months |
| Treatment-emergent adverse effects as assessed by Complete Blood Count | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Complete Blood Count | 6 Months |
| Treatment-emergent adverse effects as assessed by Complete Blood Count | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Complete Blood Count | 12 Months |
| Treatment-emergent adverse effects as assessed by C-reactive protein | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by C-reactive protein | 1 Week |
| Treatment-emergent adverse effects as assessed by C-reactive protein | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by C-reactive protein | 6 Weeks |
| Treatment-emergent adverse effects as assessed by C-reactive protein | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by C-reactive protein | 3 Months |
| Treatment-emergent adverse effects as assessed by C-reactive protein | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by C-reactive protein | 6 Months |
| Treatment-emergent adverse effects as assessed by C-reactive protein | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by C-reactive protein | 12 Months |
| Treatment-emergent adverse effects as assessed by Erythrocyte Sedimentation Rate | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Erythrocyte Sedimentation Rate | 1 Week |
| Treatment-emergent adverse effects as assessed by Erythrocyte Sedimentation Rate | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Erythrocyte Sedimentation Rate | 6 Weeks |
| Treatment-emergent adverse effects as assessed by Erythrocyte Sedimentation Rate | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Erythrocyte Sedimentation Rate | 3 Months |
| Treatment-emergent adverse effects as assessed by Erythrocyte Sedimentation Rate | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Erythrocyte Sedimentation Rate | 6 Months |
| Treatment-emergent adverse effects as assessed by Erythrocyte Sedimentation Rate | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Erythrocyte Sedimentation Rate | 12 Months |
| Treatment-emergent adverse effects as assessed by T, B and NK Cell Lymphocyte subsets | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by T, B and NK Cell Lymphocyte subsets | 1 Week |
| Treatment-emergent adverse effects as assessed by T, B and NK Cell Lymphocyte subsets | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by T, B and NK Cell Lymphocyte subsets | 6 Weeks |
| Treatment-emergent adverse effects as assessed by T, B and NK Cell Lymphocyte subsets | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by T, B and NK Cell Lymphocyte subsets | 3 Months |
| Treatment-emergent adverse effects as assessed by T, B and NK Cell Lymphocyte subsets | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by T, B and NK Cell Lymphocyte subsets | 6 Months |
| Treatment-emergent adverse effects as assessed by T, B and NK Cell Lymphocyte subsets | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by T, B and NK Cell Lymphocyte subsets | 12 Months |
| Treatment-emergent adverse effects as assessed by Serum IgG, IgA, IgM and IgE levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Serum IgG, IgA, IgM and IgE levels | 1 Week |
| Treatment-emergent adverse effects as assessed by Serum IgG, IgA, IgM and IgE levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Serum IgG, IgA, IgM and IgE levels | 6 Weeks |
| Treatment-emergent adverse effects as assessed by Serum IgG, IgA, IgM and IgE levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Serum IgG, IgA, IgM and IgE levels | 3 Months |
| Treatment-emergent adverse effects as assessed by Serum IgG, IgA, IgM and IgE levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Serum IgG, IgA, IgM and IgE levels | 6 Months |
| Treatment-emergent adverse effects as assessed by Serum IgG, IgA, IgM and IgE levels | To determine safety i.e. adverse events associated with intraarticular administration of CCM as assessed by Serum IgG, IgA, IgM and IgE levels | 12 Months |
To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. |
| Change from baseline to 24 hours after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 48 hours after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 1 week after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 6 weeks after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 3 months after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 6 months after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 12 months after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 18 months after injection |
| Change in patient reported outcome measures, Numeric Pain Rating Scale | To determine change in patient reported outcome measure, Numeric Pain Rating Scale (NPRS). A decrease in score indicates improvement. | Change from baseline to 24 months after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 1 week after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 6 weeks after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 3 months after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 6 months after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 12 months after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 18 months after injection |
| Change in patient reported outcome measures, Knee Injury and Osteoarthritis Outcome Score Jr. | To determine change in patient reported outcome measure, Knee Injury and Osteoarthritis Outcome Score Jr. (KOOS Jr.). An increase in score indicates improvement. | Change from baseline to 24 months after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 1 week after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 6 weeks after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 3 months after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 6 months after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 12 months after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 18 months after injection |
| Change in patient reported outcome measures, Patient-Reported Outcomes Measurement Information System (PROMIS) score. | To determine change in patient reported outcome measure, Patient-Reported Outcomes Measurement Information System (PROMIS) score. An increase in score indicates improvement. | Change from baseline to 24 months after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 1 Week after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 6 Weeks after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 3 Months after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 6 Months after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 12 Months after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 18 Months after injection |
| Patient Satisfaction via 5-point Likert Scale | To determine patient satisfaction via 5-point Likert Scale. An increase in score indicates improvement. | 24 Months after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 1 week after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 6 weeks after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 3 months after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 6 months after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 12 months after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 18 months after injection |
| Patient Satisfaction via Single Assessment Numeric Evaluation (SANE) | To determine patient satisfaction via Single Assessment Numeric Evaluation (SANE). An increase in score indicates improvement. | Change from baseline to 24 months after injection |
| Patient Satisfaction via 36-item short form survey (SF36) | To determine patient satisfaction via 36-item short form survey (SF36). An increase in score indicates improvement. | Change from baseline to 3 months after injection |
| Patient Satisfaction via 36-item short form survey (SF36) | To determine patient satisfaction via 36-item short form survey (SF36). An increase in score indicates improvement. | Change from baseline to 6 months after injection |
| Patient Satisfaction via 36-item short form survey (SF36) | To determine patient satisfaction via 36-item short form survey (SF36). An increase in score indicates improvement. | Change from baseline to 12 months after injection |
| Patient Satisfaction via 36-item short form survey (SF36) | To determine patient satisfaction via 36-item short form survey (SF36). An increase in score indicates improvement. | Change from baseline to 18 months after injection |
| Patient Satisfaction via 36-item short form survey (SF36) | To determine patient satisfaction via 36-item short form survey (SF36). An increase in score indicates improvement. | Change from baseline to 24 months after injection |
| Cartilage Formation | To assess cartilage formation via MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue). An increase in score indicates improvement. | Change from baseline to 12 months after injection |
| Cartilage Formation | To assess cartilage formation via MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue). An increase in score indicates improvement. | Change from baseline to 24 months after injection |
| D012216 |
| Rheumatic Diseases |