CELLULAR THERAPY CLINICAL TRIALS

The government database clinicaltrials.org lists some 4,600 clinical trials regarding cellular therapy, around 281 with results.  Below is a sample reference of the types of clinical trials available including summaries on their findings.

Vangsness CT, A Randomized Clinical Trial Using Mesenchymal Stem Cells for Meniscus Regeneration and Osteoarthritis, double-blind human trial, 55 subjects, meniscus tears, statistically significant reduction in pain from cellular therapy compared to placebo; degenerative bone changes 3.5 times more likely with placebo then cellular therapy; No serious adverse effects observed at 2 years post treatment.

Alvarez PA, Schwarz ER, Ramineni R, Myatt P, Barbin C, Boissonnet C, Phan A, Maggioni A, Barbagelata A, Peri-procedural adverse events in cell therapy trials in myocardial infarction and cardiomyopathy: a systematic reviewClin Res Cardiol. 2013 Jan, 102(1):1-10.  Summarizes data from 35 trials, covering 2,472 patients.

Richard K. Burt, MD; Yvonne Loh, MD; William Pearce, MD; Nirat Beohar, MD; Walter G. Barr, MD; Robert Craig, MD; Yanting Wen, MD; Jonathan A. Rapp, MD; John Kessler, MD , Clinical Applications of Blood-Derived and Marrow-Derived Stem Cells for Nonmalignant Diseases, JAMA. 2008;299(8):925-936. doi:10.1001/jama.299.8.925.  This summary of existing science consisted of a search of multiple electronic databases (MEDLINE, EMBASE, Science Citation Index), US Food and Drug Administration [FDA] Drug Site, and National Institutes of Health Web site to identify studies published from January 1997 to December 2007 on use of hematopoietic stem cells (HSCs) in autoimmune, cardiac, or vascular diseases. The search was augmented by hand searching of reference lists in clinical trials, review articles, proceedings booklets, FDA reports, and contact with study authors and device and pharmaceutical companies.  Evidence Synthesis Of 926 reports identified, 323 were examined for feasibility and toxicity, including those with small numbers of patients, interim or substudy reports, and reports on multiple diseases, treatment of relapse, toxicity, mechanism of action, or stem cell mobilization. Another 69 were evaluated for outcomes. For autoimmune diseases, 26 reports representing 854 patients reported treatment-related mortality of less than 1% (2/220 patients) for nonmyeloablative, less than 2% (3/197) for dose-reduced myeloablative, and 13% (13/100) for intense myeloablative regimens, ie, those including total body irradiation or high-dose busulfan. While all trials performed during the inflammatory stage of autoimmune disease suggested that transplantation of HSCs may have a potent disease-remitting effect, remission duration remains unclear, and no randomized trials have been published. For reports involving cardiovascular diseases, including 17 reports involving 1002 patients with acute myocardial infarction, 16 involving 493 patients with chronic coronary artery disease, and 3 meta-analyses, the evidence suggests that stem cell transplantation performed in patients with coronary artery disease may contribute to modest improvement in cardiac function.

 

Morikuni Tobita, et al. Adipose-Derived Stem Cells: Current Findings and Future Perspectives,Discovery Medicine; ISSN: 1539-6509; Discov Med 11(57):160-170, February 2011.  This is a summary of existing science.  Adipose Stem Cells (ASCs) hold great promise for the treatment of cardiovascular diseases and no cardiac side effects (e.g., electrical instability) have been reported to date (Bai et al., 2010). For example, a prospective, double-blind, randomized, placebo-controlled, sequential dose-escalation clinical trial is being carried out in 48 patients with acute myocardial infarction (AMI) (Sanz-Ruiz et al., 2009), and it is a trial including up to forty-eight patients. Another clinical trial with 36 patients focuses on chronic myocardial ischemia (Sanz-Ruiz et al., 2009).  ASCs were also used to heal chronic fistulas in Crohn’s disease (Garcia-Olmo et al., 2005; Garcia-Olmo et al., 2008). In a phase I trial with patients with fistulas unresponsive to standard treatment, cultured ASCs were directly injected into the rectal mucosa, and 75% of cases healed completely. In a phase IIb trial, the proportion of patients who achieved fistula healing was significantly higher with ASCs than with fibrin glue. Rigotti et al. (2007) reported successful results after injection of lipoaspirates containing ASCs to wounds caused by post-mastectomy irradiation. According to ultrastructural analysis, the early stages of tissue mesenchymalization were observed after application of lipoaspirates and a tissue resembling normal mature adipose tissue was formed at the site of application. The authors commented that this effect of lipoaspirate on wound healing was largely due to the angiogenic growth factors secreted by ASCs (Rigotti et al., 2007). These results were valuable in terms of showing the safety and feasibility of ASCs for clinical wound management (Hanson et al., 2010; Garcia-Olmo et al., 2005).

Yousef, M; Schannwell, CM; Köstering, M; Zeus, T; Brehm, M; Strauer, BE, The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction, Journal of the American College of Cardiology Jun 16, 2009, 53 (24): 2262–9.  This trial consists of 62 patients with intracoronary autologous Bone Marrow stem Cell (BMC) transplantation 7 +/- 2 days after acute myocardial infarction. Cells were infused directly into the infarct-related artery. The control group consisted of 62 patients with comparable left ventricular (LV) ejection fraction (EF) and diagnosis.  Three months after BMC therapy there was significant improvement of EF and stroke volume index. The infarct size was significantly reduced by 8%. Contraction velocities (lengths/second, volumes/second) increased significantly and the slope of the ventricular function curve (systolic pressure/end-systolic volume) became steeper. There was significant improvement of contractility in the infarct zone, as evidenced by a 31% increase of LV velocity of shortening (VCF), preferably in the border zone of the infarct zone.  The exercise capacity of treated patients was significantly augmented, and the mortality was significantly reduced in comparison with the control group.  No side effects were observed, showing that BMC therapy is safe.

Strauer, BE; Yousef, M; Schannwell, CM, The acute and long-term effects of intracoronary Stem cell Transplantation in 191 patients with chronic heARt failure: the STAR-heart study  (BM), European journal of heart failure July 2010, 12 (7): 721–9.  This trial includes 391 patients, 191 with intracoronary bone marrow stem cell therapy (and 200 placebo.  In the BMC therapy group, significant improvement in haemodynamics (e.g. LVEF, cardiac index), exercise capacity, oxygen uptake, and LV contractility were noted.  Importantly, there was a significant decrease in long-term mortality in the BMC treated patients compared with the control group.  No adverse side effects were observed.

Dr Lemuel A Moye III, Effectiveness of Stem Cell Treatment for Adults With Ischemic Cardiomyopathy (The FOCUS Study),The University of Texas Health Science Center, Houston, Clinicaltrials.gov, NCT00824005, First received: January 15, 2009, Last updated: April 2, 2013.  This trial used 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group) and no adverse effects found.

Emerson Perin, MD, PhD, Autologous Stem Cells for Cardiac Angiogenesis (FOCUS HF), Texas Heart Institute, Clinicaltrials.gov NCT00203203, First received: September 12, 2005, Last updated: April 22, 2014.  This is a phase 1, single-blind trial to evaluate using autologous bone marrow mononuclear stem cells in ischemic cardiomyopathy patients.  Cell-treated (n = 20) and control patients (n = 10) were similar at baseline. The procedure was safe; adverse events were similar in both groups. Canadian Cardiovascular Society angina score improved significantly (P = .001) in cell-treated patients, but function was not affected. Quality-of-life scores improved significantly at 6 months (P = .009 Minnesota Living with Heart Failure and P = .002 physical component of Short Form 36) over baseline in cell-treated but not control patients. Single photon emission computed tomography data suggested a trend toward improved perfusion in cell-treated patients. The proportion of fixed defects significantly increased in control (P = .02) but not in treated patients (P = .16). Furthermore, cell-treated younger patients had significantly improved maximal myocardial oxygen consumption (15 ± 5.8, 18.6 ± 2.7, and 17 ± 3.7 mL/kg per minute at baseline, 3 months, and 6 months, respectively) compared with similarly aged control patients (14.3 ± 2.5, 13.7 ± 3.7, and 14.6 ± 4.7 mL/kg per minute, P = .04).

João Tadeu Ribeiro Paes, Safety Study of Cell Therapy to Treat Chronic Obstructive Pulmonary Disease (COPD-01), UPECLIN HC FM Botucatu Unesp, NCT01110252, First received: April 20, 2010, Last updated: February 22, 2012.  The purpose of this trial was to determine whether cell therapy with bone marrow mononuclear cells is safe in the treatment of chronic obstructive pulmonary disease, specifically the pulmonary emphysema in advanced stage (stage IV dyspnea).  No adverse effects, serious or otherwise were noted.  The 12-month follow-up showed a significant improvement in the quality of life, as well as a clinical stable condition, which suggest a change in the natural process of the disease.

Makkar RR et al., Intracoronary Cardiosphere-derived Cells for Heart Regeneration after Myocardial Infarction (CADUCEUS): a Prospective, Randomized Phase I Trial, The Lancet, Early Online Publication, 14 Feb. 2012. Clinicaltrials.gov NCT00893360.  This is a phase I randomized, dose escalation study of the safety and efficacy of intracoronary delivery of cardiosphere-derived stem cells in patients with ischemic left ventricular dysfunction and a recent Myocardial Infarction (up to 12 months).  At 6 months, therapy with CSCs demonstrated to be safe and associated with increased areas of viable myocardium. Eduardo Marbán, MD, PhD, and Raj Makkar, MD stated that results from this Cedars-Sinai Heart Institute clinical trial show that an infusion of cardiac stem cells helps damaged hearts regrow healthy muscle.  The study’s findings show that heart attack patients who received stem cell treatment demonstrated a significant reduction in the size of the scar left on the heart muscle; this is a pioneering stem cell result, says Marban, who notes the study shows actual regeneration of tissues.  The process to grow cardiac-derived stem cells involved in the study was developed earlier by Marbán when he was on the faculty of Johns Hopkins University.

Sanchez PL et al., Cultured and Freshly Isolated Adipose Tissue-derived Cells: Fat Years for Cardiac Stem Cell Therapy, Eur Heart J. 2009;31:394-7.  PRECISE was a prospective double-blind, randomized, placebo-controlled, sequential dose-escalation trial randomizing patients with end-stage CAD not amenable to revascularization and with moderate-severed left ventricular dysfunction to received freshly isolated ASCs or placebo in a 3:1 ratio.  The cells were delivered via trnasendocardial injections after left ventricle electromechnical mapping.  Preliminary results suggest that ASCs therapy is safe and results in a stabilization of infarct size and improvement in maximal oxygen consumption.

Duckers J et al., First-in-man Experience with Intracoronary Infusion of Adipose-derived Regenerative Cells in the Treatment of Patients with ST-elevation Myocardial Infarction: the Apollo Trial, Circulation. 2010; 120:Article ID A12225.  APOLLO (Clinicaltrials.gov NCT00442806) was a prospective, double-blind, randomized, placebo-controlled, sequential dose-escalation trial in which ASCs were delivery through intracoronary infusion after appropriate infarct-related artery therapy with stent implantation.  This study aimed to investigate the benefits of ASCs in patients with acute Myocardial Infarction (MI) and LVEF impairment.  Preliminary results confirm safety.  Now, a phase II/II ADVANCE trial has been initiated to evaluate their efficacy (Clinicaltrials.gov NCT01216995)

Kurata Hayato et al., Adipose Tissue-derived Mesenchymal Stem Cells in Regenerative Medicine Treatment for Liver Cirrhosis – Focused on Efficacy and Safety in Preclinical and Clinical Studies,SciMedCentral, March 2014. According to the clinical trials using bone marrow stem cells and umbilical cord mesenchymal stem cells, these cells are effective for treating patients with severe liver disease and do not have obvious side effects.  This study focuses on determining if adipose stem cells have similar positive effects.

Guoping Zheng, Lanfang Huang, [...], and Jianguo Xu , Treatment of Acute Respiratory Distress Syndrome with Allogeneic Adipose-derived Mesenchymal Stem Cells: a Randomized, Placebo-controlled Pilot Study, Respir. Res. 2014; 15(1); 39.; Clinical trials.gov, NCT01902082.  Administration of allogeneic adipose-derived MSCs appears to be safe and feasible in the treatment of ARDS.  There were no infusion toxicities or serious adverse events related to MSCs administration, nor significant differences in the overall number of adverse events between the two group.

Chen SL et al., Effect on Left Ventricular Function of Intracoronary Transplantation of Autologous Bone Marrow Mesenchymal Stem Cell in Patients with Acute Myocardial Infarction, Am J cardiol. 2004;94:92-5. Intracoronary injection of a large number of BM-derived MSCs resulted in improvement in global LVEF and regional wall motion, and reduction in infarct size, LVESC, as well as LVEDV in patients with acute Myocardial Infarction (MI).

Chen et al., Intracoronary Transplantation of Autologous Bone Marrow Mesenchymal Stem Cells for Ischemic Cardiomyopathy Due to Isolated Chronic Occluded Left Anterior Descending Artery, J. Invasive Cardiol. 2006;18:552-6.  This randomized studies investigated the use of MSCs in patients with chronic CAD.  It demonstrated that intracoronary injection of culture-expanded MSCs in patients after percutaneous coronary intervention (PCI) of the chronically occluded left anterior descending artery improved myocardial perfusion, improved exercise tolerance and NYHA class and LVEF in treated patients.  Two studies NCT00587990 and NCT00418418 are currently registered for MSC intramyocardial injections in conjunction with CABG in patients with ischemic heart failure, focusing on efficacy and safety.

Hare JM et al., A Randomized, Double-blind, Placebo-controlled, Dose Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) after Acute Myocardial Infarction, J Am Coll Cardiol. 2009;54:2277-86.  A randomized clinical trial using MSCs in post-infarct patients demonstrated that intravenous allogeneic hMSCs is safe.  In this study, the global symptom score, defined from subject interviews at day 10 and 6 months after treatment compared with pretreatment, was better in MSCs versus placebo (p=0.027), while the LVEF was significantly better only in the subset of anterior Myocardial Infarction (MI) patients compared to control.  A follow-on on-going phase II, multi-center, randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of ex vivo cultured adult human MSCs intravenous infusion following acute MI is expecting to recruit around 300 patients (Clinicaltrials.gov NC00877903)

Peter Connick, Madhan Kolappan, [...], and Siddharthan Chandran,  Autologous Mesenchymal Stem Cells for the Treatment of Secondary Progressive Multiple Sclerosis: an Open-label Phase 2a Proof-of-concept Study, This trial is registered with ClinicalTrials.gov, number NCT00395200. This study shows that after intravenous administration of autologous mesenchymal stem cells, patients with secondary progressive disease improved on measures of visual function, physiology, and structure without evidence of significant adverse events.  The authors searched Medline (1950 to August, 2011), Embase (1980 to August, 2011), and the Cochrane Central Register of Controlled Trials (The Cochrane Library issue 4, 2011) with the terms “multiple sclerosis” and “mesenchymal stem cells” for clinical trials.  They identified three published trials.  Consistent with previous studies, their findings show that intravenous administration of autologous mesenchymal stem cells to patients with secondary progressive multiple sclerosis is feasible and safe. Their findings also suggest structural, functional, and physiological improvement after treatment consistent with neuroprotection.

Wang XX et al., Transplantation of Autologous Endothelial Progenitor Cells may be Beneficial in Patients with Idiopathic Pulmonary Arterial Hypertension: a Pilot Randomized Controlled Trial, J Am Coll Cardiol. 2007;49:1566-71

and

Zhu JH et al., Safety and Efficacy of Autologous Endothelial Progenitor Cells Transplantation in Children with Idiopathic Pulmonary Arterial Hypertension: Open-label Pilot Study. Pediatr Transplant. 2008;12:650-5

These two studies in adults and in children with idiopathic PH have evaluated the efficacy of therapy with a single intravenous infusion of autologous mononuclear cells.  In the adult patients (n=15), at twelve weeks, this therapy resulted in improvement in the six-minute walk test distance (42.5 mean; 28.7 to 56.3; 95% CI; p=0.001), reduced mean pulmonary artery pressure (-4.0 mm Hg, -6.2 to -1.9; 95% CI; p=0.001) and pulmonary vascular resistance (-157 dyn/s/cm5; -250 to -65; 95% CI; p=0.002), and increased cardiac output (0.32 L/min; 0.05 to 0.59; 95% CI; p=0.021), compared with patients receiving conventional therapy (n=16).  Similar responses were also found in children.  Importantly, no undesirable effects of cell-based therapies were described.  Currently, a phase I trial to establish safety… is being conducted in Canada (PHACeT trial, NCT00469027).

SCHEDULE FOR A FREE CONSULTATION

TOP