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Brain injuries resulting from motor vehicle accidents and falls, as well as hypoxic insults and other conditions, are one of the leading causes of disability and death in the world. Current treatments are limited but include continuous rehabilitation, especially for chronic brain injury. Recent studies have demonstrated that the intravenous infusion of mesenchymal stem cells (MSCs) has therapeutic efficacy for several neurological diseases, including stroke and spinal cord injury.
The objective of our investigator-initiated clinical trial is to assess the safety and potential efficacy of the intravenous infusion of autoserum-expanded autologous MSCs for patients with chronic brain injury.
The (phase 2) trial will be a single-arm, open-label trial with the primary objective of confirming the safety and efficacy of autoserum-expanded autologous MSCs (STR-01; produced under good manufacturing practices) when administered to patients with chronic brain injury. The estimated number of enrolled participants is 6 to 20 patients with a modified Rankin Scale grade of 3 to 5. The assessment of safety and the proportion of cases in which the modified Rankin Scale grade improves by 1 point or more at 180 days after the injection of STR-01 will be performed after MSC infusion.
We received approval for our clinical trial from the Japanese Pharmaceuticals and Medical Devices Agency on December 12, 2017. The trial will be completed on June 11, 2023. The registration term is 5 years. The recruitment of the patients for this trial started on April 20, 2018, at Sapporo Medical University Hospital in Japan.
Our phase 2 study will aim to address the safety and efficacy of the intravenous infusion of MSCs for patients with chronic brain injury. The use of STR-01 has been performed for patients with cerebral infarction and spinal cord injury, providing encouraging results. The potential therapeutic efficacy of the systemic administration of autoserum-expanded autologous MSCs for chronic brain injury should be evaluated, given its safety and promising results for stroke and spinal cord injury.
Japan Medical Association Center for Clinical Trials JMA-IIA00333; https://tinyurl.com/nzkdfnbc
DERR1-10.2196/37898
A
The intravenous infusion of mesenchymal stem cells (MSCs) has shown therapeutic efficacy in experimental animal models of neurological diseases and injuries, including cerebral ischemia [
The objectives of the proposed clinical trial include evaluating the safety and efficacy of intravenously infused autologous MSCs that are expanded with autosera in patients with chronic brain injury.
The (phase 2) trial will be a single-arm, open-label trial. The outline of the clinical protocol is shown in
Clinical protocol. FMA: Fugl-Meyer assessment; MSC: mesenchymal stem cell.
We propose to provide an extensive rehabilitation protocol to all participants prior to MSC infusion in order to exclude the potential effects of rehabilitation alone and evaluate MSC-specific effects. Briefly, all patients with chronic brain injury will receive formal rehabilitation (at least 80 min/weekday for 4 weeks) and continue formal rehabilitation until they show no further improvements in Fugl-Meyer assessment (FMA) scores for the last 2 weeks prior to MSC infusion. Thus, we expect to evaluate the therapeutic effects of MSC infusion in addition to the effects of rehabilitation therapy. We will evaluate FMA scores approximately every week. The clinical data will be collected by at least 1 physical therapist and at least 1 Japanese board-certified neurosurgeon at Sapporo Medical University Hospital. If the patients require more than 2 weeks to reach an FMA score plateau, we will continue formal rehabilitation until they show no further improvements for the next 2 weeks.
For cell preparation, peripheral blood draws from each patient for autoserum and bone marrow collection will be performed. The autologous MSCs will be cultured in autologous sera, and the autologous human MSCs (called
We will recruit 10 people (minimum: 6; maximum: 20) with a modified Rankin Scale (mRS) grade of 3 to 5. The focus of our trial is to establish safety and potential efficacy. However, it should be noted that if the proportion of cases in which the mRS grade improves by 1 point or more exceeds 10%, the trial will provide significant clinical benefit. To detect a difference by using a
This study protocol was approved by the institutional review board (IRB) at Sapporo Medical University Hospital (approval number: 29-15). Changes to the protocol will require IRB and Japanese PMDA approval. The trial will be conducted in accordance with the ethical principles of the Declaration of Helsinki, the Japanese Pharmaceutical Affairs Law, and good clinical practice. Trial investigators will obtain written informed consent from each participant before study inclusion. If the participants do not have the ability to write, written informed consent will be obtained from a legal representative alone. Participants will be free to withdraw from the study at any time.
The results from our study will be presented in peer-reviewed publications and meetings without identifying data. Written consent for publication will be obtained from all participants in the study.
Since MSCs will be collected from the participants (autologous MSCs) in our study, we must start the MSC cultures after primary registration in order to initiate the collection of peripheral blood and bone marrow when the protocol therapy starts. Afterward, we must confirm that the MSC product passed the shipping standards before infusion. Thus, we must perform a secondary registration of the participants. Therefore, case registration will require 2 steps in the trial; we will register the participants before blood and bone marrow collections (first registration) and before the infusion of MSCs (second registration).
For the first registration, the inclusion criteria will be as follows: (1) a brain injury oth.er than stroke diagnosed via magnetic resonance imaging (MRI), computed tomography, 3D computed tomography angiography (3D-CTA), or angiography (including a suspected brain injury other than stroke); (2) a classification of grade 3 to 5 on the mRS; (3) patients aged 20 to 80 years; (4) patients whose rehabilitation can be performed for at least 80 minutes per weekday; and (5) written informed consent, which will be obtained as much as possible from the participants. If a participant does not have ability to write, written informed consent will be obtained from a legal representative alone.
For the first registration, the exclusion criteria will be as follows:
Severe disturbance of consciousness (a Japan Coma Scale score of between 200 and 300)
Severe contracture, deformity, or calcification of a joint
Diagnosed with hepatitis B, hepatitis C, or syphilis via initial screening
Pancytopenia (a white blood cell concentration of <2000 cells/µL, hemoglobin concentration of <10.0 g/dl, or platelet concentration of <100,000 platelets/µL)
MRI (or computed tomography) scan revealing a severe asymptomatic lesion or white matter lesion
MRI scan revealing multiple and severe instances of microbleeding or hemosiderosis in the whole brain
Head and neck magnetic resonance angiography (or 3D-CTA or angiography) scan revealing ≥70% stenosis of main cerebral arteries and cervical carotid arteries even after the revascularization (except for complete occlusion) or dissection of an artery
Head and neck magnetic resonance angiography (or 3D-CTA or angiography) scan revealing severe arteriosclerotic change or severe calcification
Moyamoya disease, cerebral aneurysm, and other vascular malformations with a high risk of rupture or cerebral embolism
Uncontrollable hypertension with therapy prior to infusion (systolic pressure: >140 mm Hg; diastolic pressure: >90 mm Hg)
Past history of neoplasms (except complete response); severe diseases of the blood and blood-forming organs; certain disorders involving the immune mechanism; severe mental and behavioral disorders; severe diseases of the nervous system; and severe congenital malformations, deformations, and chromosomal abnormalities
Past history of penicillin and streptomycin allergy or other severe allergy (shock or anaphylactic symptoms)
Poor general condition due to endocrine, nutritional, and metabolic diseases; uncontrollable mental disorders; diseases of the nervous system (refractory epilepsy), diseases of the circulatory system (uncontrollable and refractory heart failure, moderate or severe valvular heart disorder, uncontrollable and refractory atrial fibrillation, refractory atrial and ventricular thrombi, a history of ischemic heart disease with percutaneous coronary intervention within the past 12 months, and serious arrhythmia); diseases of the respiratory system; diseases of the digestive system; diseases of the musculoskeletal system and connective tissue; diseases of the genitourinary system (dialysis); injury; poisoning; and certain other consequences of external causes
Participation in another clinical trial related to any organ or a past history of cellular therapy
Pregnant or possibly pregnant women, nursing women, women who plan to be pregnant during the study period, or male patients who want their partners to get pregnant
Other patients who are judged by investigators holding a medical license as inappropriate for the study
For the second registration, the inclusion criteria will be as follows: (1) ≥180 days after the onset of a brain injury other than stroke; (2) patients who, after rehabilitation for at least 80 minutes per weekday or as much as possible over the past 1 month or more, showed no improvement in FMA score over the last 2 weeks (definition of
For the second registration, the exclusion criteria will be as follows:
Severe disturbance of consciousness (Japan Coma Scale score of between 200 and 300)
Diagnosed with hepatitis B, hepatitis C, HIV, human T-lymphotropic virus 1 infection, syphilis, or human parvovirus B19 infection via detailed examination
More than 70% stenosis of main cerebral arteries and cervical carotid and vertebral arteries even after the revascularization (except for complete occlusion and a healed dissecting artery) or dissection of an artery
Severe arteriosclerotic change and calcification
Moyamoya disease, cerebral aneurysm, or other vascular malformations with a high risk of rupture or cerebral embolism
Uncontrollable hypertension with therapy prior to infusion
Ischemic heart disease (more than 75% stenosis of coronary arteries)
Cardiac shunt malformation (ventricular septal defect or arterial septal defect)
Possible large thrombus, as determined via laboratory examination
Neoplasms (except complete response); severe diseases of the blood and blood-forming organs; certain disorders involving the immune mechanism; severe mental and behavioral disorders; severe diseases of the nervous system; and severe congenital malformations, deformations, and chromosomal abnormalities
Penicillin and streptomycin allergy and other severe allergy (shock or anaphylactic symptoms)
Poor general condition due to endocrine, nutritional, and metabolic diseases; uncontrollable mental disorders; diseases of the nervous system (refractory epilepsy), diseases of the circulatory system (uncontrollable and refractory heart failure, moderate or severe valvular heart disorder, uncontrollable and refractory atrial fibrillation, refractory atrial and ventricular thrombi, a history of ischemic heart disease and percutaneous coronary intervention within the past 12 months, and serious arrhythmia); diseases of the respiratory system; diseases of the digestive system; diseases of the musculoskeletal system and connective tissue; diseases of the genitourinary system (dialysis); injury; poisoning; and certain other consequences of external causes
Pregnant women, nursing women, those who plan to be pregnant during the study period, or male patients who want their partners to get pregnant
Other patients who are judged by investigators holding a medical license as inappropriate for the study
Outcome measures will be performed by more than 2 Japanese board-certified neurosurgeons at Sapporo Medical University Hospital
The primary outcome is the proportion of cases in which the mRS grade improves by 1 point or more between 180 (±14) days after the injection of STR-01 and just before injection (−14 to 0 days).
The following are the secondary outcomes: (1) the rate of all adverse events during the whole study period, (2) the differences in FMA scores (each item score and total score) between 180 (±14) days after the injection of STR-01 and just before injection (−14 to 0 days), (3) the differences in National Institutes of Health Stroke Scale scores (each item score and total score) between 180 (±14) days after the injection of STR-01 and just before injection (−14 to 0 days), and (4) the differences in Functional Independence Measure scores (each item score and total score) between 180 (±14) days after the injection of STR-01 and just before injection (−14 to 0 days).
The plan of analysis for study data will be performed by a biomedical statistician (YMI), and statistical analyses will be performed by using JMP 11.1 for Windows (SAS Institute Inc). The details are described in our statistical analysis plan and are described briefly in the following subsections.
The valid target population is patients with an mRS grade of 3 to 5 before MSC infusion. We assume that the proportion of cases without MSC infusion in which the mRS grade improves by 1 point or more will be 0.1%. We will perform a Z-test with continuity correction at 180 (±14) days after MSC infusion.
We will estimate the proportion of cases with at least 1 level of improvement in mRS grade and the 95% CI by using the scoring method at 180 (±14) days after MSC infusion. We will also estimate the mean changes in FMA, National Institutes of Health Stroke Scale, and Functional Independence Measure scores from immediately before (−14 to 0 days) MSC infusion to 180 (±14) days after MSC infusion and the 95% CIs by using the Wald method.
The participants of the trial will follow standard clinical procedures during the study; thus, there will be no specific posttrial care. As the participants are the patients within Japan’s National Health Insurance system, postcare will be provided through the National Health Insurance schemes, if necessary. Clinical research insurance for studies will also be covered.
All investigators will have access to the trial data.
All participant trial data will be entered into the electronic data capture system hosted at the Translational Research Center for Medical Innovation (Kobe, Japan). The data collected will be deidentified by using unique study code numbers. To maintain the privacy of the participants, any reports of individual data will only consist of clinical data without any names, addresses, or identifying information. This complies with the university’s IRB guidelines. All patient-related information and data that are generated will be maintained on a secure server. Data monitoring will comply with the university’s policies, its guidelines, and the data management plan that was approved for the study. Data will be audited at an appropriate period by the EPS Corporation (Tokyo, Japan). At the completion of the study, the results will be submitted for publication in a peer-reviewed journal and presented at national and international conferences.
We received approval for our clinical trial from the Japanese PMDA on December 12, 2017. The trial will be completed on June 11, 2023. The registration term is 5 years. The recruitment of the patients for this trial started on April 20, 2018, at Sapporo Medical University Hospital in Japan.
The specific objective of our trial is to evaluate the safety and potential therapeutic efficacy of the intravenous infusion of autoserum-expanded autologous MSCs for patients with chronic brain injury. The patients who enrolled in our study with chronic brain injury and decreased neural function due mainly to brain trauma will receive an intravenous infusion of autologous MSCs that are expanded in autosera. A brain injury presents serious health and socioeconomic burdens that the development of an effective therapy could alleviate.
Various treatments have been developed that focus mainly on the acute phase, including neurorestorative, anti-inflammatory, and neuroprotective agents. However, no established medical therapies that promote effective therapeutic efficacy have been made, especially for the chronic phase. Therefore, a novel therapy that promotes recovery from brain damage after a chronic brain injury should be developed [
We previously reported on the safety, feasibility, and potential therapeutic efficacy of the intravenous infusion of autoserum-expanded autologous MSCs for patients with cerebral infarction [
We reported that infused MSCs facilitate neural plasticity in experimental models of neonatal [
The purpose of our study is to address the safety and potential therapeutic efficacy of the intravenous infusion of autologous MSCs based on the primary outcome measures. If the intravenous infusion of autologous MSCs shows possible therapeutic efficacy and is shown to be safe without any major adverse effects, this approach could be successfully translated to a larger controlled and blinded clinical study in the future. The data from our study will be used to develop a new clinical protocol for any future, larger, definitive evaluation trials.
In conclusion, due to the promising therapeutic effects of autoserum-expanded autologous MSCs for stroke [
3D computed tomography angiography
Fugl-Meyer assessment
institutional review board
magnetic resonance imaging
modified Rankin Scale
mesenchymal stem cell
Pharmaceuticals and Medical Devices Agency
spinal cord injury
The authors thank the members of the cell processing center and the Center for Clinical Trials at Sapporo Medical University, as well as Rehabilitation Center for Traumatic Apallics Chiba, National Agency for Automotive Safety and Victims' Aid.
The development of autologous mesenchymal stem cells cultured in autosera was supported by the Japanese Ministry of Education, Culture, Sports, Science and Technology (Coordination, Support and Training Program for Translational Research; grants 20390388 and 09025015). This work was supported in part by the funding for education and research at Sapporo Medical University, the Agency for Medical Research and Development Translational Research Network Program (grant JP16lm0103003), and Nipro Corporation. Nipro will not have access to the results. The funders had no influence on the design of the protocol, and they will not have any impact on data generation, statistical analyses, or the writing of the final manuscript.
OH is responsible for the processing of the trial. RO and OH wrote and reviewed all protocol versions. SO, MS, RU, MT, TY, YKS, JDK, and OH reviewed all protocol versions. SO, TY, MS, RU, MT, TY, YKS, YMI, SK, YI, and OH participated in the conduction of the trial. All authors read and approved the final manuscript.
The Department of Advanced Regenerative Therapeutics at Sapporo Medical University has been partnered with the Nipro Corporation since February 1, 2014. Sapporo Medical University and Nipro Corporation entered into a joint research and development agreement on April 1, 2014, which provides research support to the department, including support for the work carried out by some of the coauthors (SO, MS, YKS, and OH). JDK receives research support through Yale University from the Nipro Corporation for associated research on preclinical studies of rodent mesenchymal stem cells. YT, RU, MT, TY, RO, YMI, SK, and YI report no competing interests.