Evaluation of Safety and Efficacy of Cell Therapy Based on Osteoblast Derived from Umbilical Cord Mesenchymal Stem Cell for Osteonecrosis of the Femoral Head: Study Protocol for a Single-Center, Open-Label, Phase I Clinical Trial

Abstract BackgroundVarious techniques for joint preservation have been attempted in early stage of osteonecrosis of femoral head (ONFH), but the effects are still controversial. Recently, a combination therapy of core decompression (CD) and MSCs collected from bone marrow, adipocytes or human umbilical cord has been introduced, and satisfactory results have been reported. However, there is no study in which human umbilical cord-derived osteoblasts (hUC-O) were administered directly to the lesion in early ONFH. We have classified the location and size of lesions in early-stage ONFH, and will evaluate the hypothesis that the application of hUC-O is a safe and effective treatment.MethodsThis is a prospective, single-center, phase I and open-labeled clinical trial. Nine patients with Association Research Circulation Osseous (ARCO) stage 1 or 2 ONFH will be assigned to a low-dose (n = 3, 1 ´ 107 hUC-O cells), medium-dose (n = 3, 2 ´ 107 cells), and high-dose group (n = 3, 4 ´ 107 cells) in the order of their arrival at the facility, and up to 18 patients will be enrolled depending on whether dose limiting toxicity occurs. We will perform CD on the participants, administer hUC-O according to the assigned group, and followed up for 12 weeks, including a total of 5 visits. This study will have 3 aims; first, to evaluate the safety of hUC-O through adverse events assessment, laboratory tests, vital sign assessment, physical examination, and electrocardiogram (ECG) test.; and second, to assess the clinical outcomes after hUC-O application by comparing pain visual analog scale (VAS), Harris Hip scores (HHS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) before and after surgery; and third, to evaluate the radiographic results after hUC-O application by comparing extent of necrotic lesions according to the ARCO and Japanese Investigation Committee (JIC) classification on magnetic resonance imaging.DiscussionThis clinical trial is a pilot phase 1 study evaluating the safety and efficacy of hUC-O local application combined with CD in early-stage ONFH patients. This study will provide the useful information on the treatment with hUC-O for those suffering from ONFH.Trial registration: Clinical Research Information Center (CRIS) established at the Korea Centers for Disease Control and Prevention (KDCA), KCT0006627. Registered 30 September 2021, https://cris.nih.go.kr/cris/search/detailSearch.do/20332

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Cell-Based Regenerative Endodontics for Treatment of Periapical Lesions: A Randomized, Controlled Phase I/II Clinical Trial

Journal of Dental Research ◽

10.1177/0022034520913242 ◽

2020 ◽

Vol 99 (5) ◽

pp. 523-529 ◽

Cited By ~ 4

Author(s):

C. Brizuela ◽

G. Meza ◽

D. Urrejola ◽

M.A. Quezada ◽

G. Concha ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Phase I ◽

Umbilical Cord ◽

Root Canal ◽

Categorical Variables ◽

Safety And Efficacy ◽

Randomized Controlled

A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher’s exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

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Human Umbilical Cord Mesenchymal Stem Cells to Treat Neuromyelitis Optica Spectrum Disorder (hUC-MSC-NMOSD): A Study Protocol for a Prospective, Multicenter, Randomized, Placebo-Controlled Clinical Trial

10.21203/rs.3.rs-131661/v1 ◽

2020 ◽

Author(s):

Xiaoying Yao ◽

Li Xie ◽

Yu Cai ◽

Ying Zhang ◽

Ye Deng ◽

...

Keyword(s):

Clinical Trial ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Umbilical Cord ◽

Dose Group ◽

Optimal Dose ◽

Controlled Clinical Trial ◽

High Dose ◽

Human Umbilical Cord ◽

Neuromyelitis Optica Spectrum Disorder

Abstract Background：Neuromyelitis optica spectrum disorder (NMOSD) is a severe relapsing and disabling inflammatory autoimmune disease of the central nervous system. Despite the progress made in understanding the pathogenesis of the disease, the optimal first line treatment to reduce relapse rate and ameliorate neurological disability remains unclear. Mesenchymal stem cells (MSC) are known for having anti-inflammatory and regenerative properties and there are a number of studies on the use of human umbilical cord MSCs (hUC-MSCs) in NMOSD patients. Therefore, we will conduct a prospective, multicenter, randomized, placebo-controlled clinical trial to study the safety and effectiveness of hUC-MSCs in the treatment of NMOSD.Methods：The trial is planned to recruit 430 AQP4-IgG seropositive NMOSD patients. The multicenter study will be conducted in six clinical centers. The whole clinical trial consists of three consecutive stages. The first stage will be carried out in the leading center (Ren Ji Hospital) only and it will last 24 months. In the first stage the primary objective is to evaluate the safety of hUC-MSCs. Patients (n=30) will be treated with three different doses of hUC-MSC: the low dose group (n=10, 1×106 MSC / kg·weight), the medium dose group (n=10, 2×106 MSC / kg·weight) and the high dose group (n=10, 5×106 MSC / kg·weight). The second stage, which aims to find the optimal dosage, will last 24 months and will be carried out in six centers (one leading center and five branch centers). Patients (n=160) will be randomized into four groups by 1:1:1:1 allocation ratio: the low, medium, high dose groups and the controlled group (n=40). The third stage, which aims to evaluate the effectiveness, will lasts for 24 months and will be developed in six centers. Patients (n=320) will be 1:1 randomized into two groups: the optimal dose group (n=160) and the controlled group (n=160). HUC-MSC infusion will be given four times to the intervention groups and stem cell solution will be given four times to the control group every 3 months; besides the primary drugs will be provided to both groups. Primary endpoint is the first recurrent time and secondary endpoints are the recurrent times, EDSS scores, MRI lesion numbers, OSIS scores, Hauser walking index and SF-36 (quality of life short Form-36) scores. Exploratory endpoints will include: serum lymphocyte subsets, cytokines, complements, serum anti-AQP4 antibody titers etc. Endpoint events and side-effects will be evaluated at baseline and every 3 months for a total of 24 months follow-up.Discussion：Although hUC-MSC has shown promising treatment effect of NMOSD in preclinical study, there is still a lack of well-designed clinical trials to evaluate the safety and effectiveness of hUC-MSC among NMOSD patients. As far as we know, this trial will be the first one to systematically demonstrate the clinical safety and efficacy of hUC-MSC in treating NMOSD and might be able to determine the optimal dose of hUC-MSC for NMOSD patients.Trial registration：The study was registered with Chinese Clinical Trial Registry (CHICTR.org.cn) on Mar 2, 2016 (registration No. ChiCTR-INR-16008037), and the revised trial protocol (Protocol version 1.2.1) was released on March 16, 2020.

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Safety and Efficacy of Intravenous Ultra-high Dose Methylcobalamin Treatment for Peripheral Neuropathy: A Phase I/II Open Label Clinical Trial

Internal Medicine ◽

10.2169/internalmedicine.53.1951 ◽

2014 ◽

Vol 53 (17) ◽

pp. 1927-1931 ◽

Cited By ~ 13

Author(s):

Kazumoto Shibuya ◽

Sonoko Misawa ◽

Saiko Nasu ◽

Yukari Sekiguchi ◽

Minako Beppu ◽

...

Keyword(s):

Clinical Trial ◽

Peripheral Neuropathy ◽

Phase I ◽

High Dose ◽

Open Label ◽

Safety And Efficacy

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Continuous intravenous vitamin C in the cancer treatment: re-evaluation of a Phase I clinical study

Functional Foods in Health and Disease ◽

10.31989/ffhd.v9i3.590 ◽

2019 ◽

Vol 9 (3) ◽

pp. 180

Author(s):

Nina Mikirova ◽

Joseph Casciari ◽

Ronald Hunninghake

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Vitamin C ◽

Phase I ◽

Cancer Patients ◽

Phase 1 ◽

Cancer Prognosis ◽

Sodium Ascorbate ◽

High Dose ◽

Treatment Schedule

Background: Intravenous high-dose vitamin C (IVC) therapy is widely used in naturopathic and integrative oncology. A number of Phase I and Phase II clinical trials were launched to prove the benefits of the IVC therapy. Many case studies demonstrated the effectiveness of IVC, with various degrees of success. Clinical trials using IVC to treat cancer have, to date, demonstrated its safety without conclusively proven its efficacy. One difficulty in administering IVC is determining the optimal treatment schedule. To this end, data from a previous Phase 1 clinical trial conducted in 1998 using continuous vitamin C infusions was analyzed to examine the effects of this regimen on key prognostic parameters. Method: Twenty-four subjects were given continuous IVC at doses between 150 and 710 mg/kg/day. Most of the patients had colon cancer with liver and lung metastasis and three patients had pancreatic or liver cancer. All patients had several chemotherapy/radiation treatments before entering the study. Patients were treated by pharmaceutical grade sodium ascorbate diluted in Lactated Ringers solution with the rate of infusion of 20 ml/hr or 10 ml/hr for lower doses. This diluted solution was administered by continuous infusion.Results: Prior to treatment, serum lymphocyte counts and ascorbate concentrations tended to be low while serum levels of lactate dehydrogenase (LDH), neutrophils, and glucose tended to be high. Improvements were seen during IVC therapy. In patients with initially elevated neutrophil levels, numbers tended to decrease. In contrast, increased absolute neutrophil and lymphocyte numbers were seen in patients with initially low counts. Neutrophil to lymphocyte ratios (NLR) proved to be a good indicator of cancer patients’ survival times (high NLR, low survival). This was also true of LDH, creatinine, and glucose concentrations. In patients with the highest pre-treatment NLR, rate of growth of this ratio decreased significantly during therapy. IVC treatments were also associated with decreases in glucose concentrations, restoration of vitamin C levels, and, in about 40% of cases, reductions in LDH levels. Conclusions: As the result of the study we found that continuous IVC infusions improved several parameters associated with poor cancer prognosis. The data suggests a strategic benefit to using lower IVC doses in continuous infusions: raising the dose above 300 mg/kg/day (20 grams in 70 kg human) increased the frequency of side effects without noticeably increasing plasma ascorbate levels. Moreover, improvements in lymphocyte counts at low IVC doses tended to decrease at the higher doses. In conclusion, continuous infusions had benefits to cancer patients and further research in this area is warranted.Keywords: ascorbic acid; continuous infusion; cancer patients; clinical trial; lymphopenia; neutrophil to lymphocyte ratio; hyperglycemia; safety.

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