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1.  Factors affecting the Turnaround Time for Manufacturing, Testing and Release of Cellular Therapy Products prepared at Multiple Sites in support of Multicenter Cardiovascular Regenerative Medicine Protocols – a Cardiovascular Cell Therapy Research Network (CCTRN) Study 
Transfusion  2012;52(10):2225-2233.
BACKGROUND
Cellular therapy studies are often conducted at multiple clinical sites in order to accrue larger patient numbers. In many cases this necessitates use of localized Good Manufacturing Practices (GMP) facilities to supply the cells. To assure consistent quality, oversight by a quality assurance group is advisable. In this study we report the findings of such a group established as part of the Cardiovascular Cell Therapy Research Network (CCTRN) studies involving use of autologous bone marrow mononuclear cells (ABMMC) to treat myocardial infarction and heart failure.
STUDY DESIGN
Factors affecting cell manufacturing time were studied in 269 patients enrolled on 3 CCTRN protocols using Sepax-separated ABMMC. The cells were prepared at 5 GMP cell processing facilities and delivered to local treatment sites or more distant satellite Centers.
RESULTS
Although the Sepax procedure takes only 90 minutes, the total time for processing was approximately seven hours. Contributing to this were incoming testing and device preparation, release testing, patient randomization and product delivery. The average out-of body-time (OBT), which was to be <12 hours, averaged 9 hours. A detailed analysis of practices at each Center revealed a variety of factors that contributed to this OBT.
CONCLUSION
We conclude that rapid cell enrichment procedures may give a false impression of the time actually required to prepare a cellular therapy product for release and administration. Institutional procedures also differ and can contribute to delays; however, in aggregate it is possible to achieve an overall manufacturing and testing time that is similar at multiple facilities.
doi:10.1111/j.1537-2995.2011.03543.x
PMCID: PMC3355200  PMID: 22320233
Cellular therapy; Regenerative medicine; Cardiovascular cell therapy; Turnaround time
2.  Cell tracking and the development of cell-based therapies: a view from the Cardiovascular Cell Therapy Research Network 
JACC. Cardiovascular imaging  2012;5(5):559-565.
Cell-based therapies are being developed for myocardial infarction (MI) and its consequences (e.g. heart failure) as well as refractory angina and critical limb ischemia. The promising results obtained in pre-clinical studies led to the translation of this strategy to clinical studies. To date, the initial results have been mixed: some studies showed benefit, while in others no benefit was observed. There is a growing consensus among the scientific community that a better understanding of the fate of transplanted cells (e.g., cell homing and viability over time) will be critical for the long term success of these strategies and that future studies should include an assessment of cell homing, engraftment and fate as an integral part of the trial design. In this review, different imaging methods and technologies will be discussed within the framework of the physiological answers that the imaging strategies can provide, with special focus on the inherent regulatory issues.
doi:10.1016/j.jcmg.2011.12.018
PMCID: PMC3632261  PMID: 22595165
3.  Multicenter Cell Processing for Cardiovascular Regenerative Medicine Applications - The Cardiovascular Cell Therapy Research Network (CCTRN) Experience 
Cytotherapy  2010;12(5):684-691.
Background Aims
Multi-center cellular therapy clinical trials require the establishment and implementation of standardized cell processing protocols and associated quality control mechanisms. The aims here were to develop such an infrastructure in support of the Cardiovascular Cell Therapy Research Network (CCTRN) and to report on the results of processing for the first 60 patients.
Methods
Standardized cell preparations, consisting of autologous bone marrow mononuclear cells, prepared using the Sepax device were manufactured at each of the five processing facilities that supported the clinical treatment centers. Processing staff underwent centralized training that included proficiency evaluation. Quality was subsequently monitored by a central quality control program that included product evaluation by the CCTRN biorepositories.
Results
Data from the first 60 procedures demonstrate that uniform products, that met all release criteria, could be manufactured at all five sites within 7 hours of receipt of the bone marrow. Uniformity was facilitated by use of the automated systems (the Sepax for processing and the Endosafe device for endotoxin testing), standardized procedures and centralized quality control.
Conclusions
Complex multicenter cell therapy and regenerative medicine protocols can, where necessary, successfully utilize local processing facilities once an effective infrastructure is in place to provide training, and quality control.
doi:10.3109/14653249.2010.487900
PMCID: PMC3600982  PMID: 20524773
cell therapy; regenerative medicine; multicenter trials; cardiac cell therapy; quality control; Sepax
4.  Developing Mechanistic Insights into Cardiovascular Cell Therapy: Cardiovascular Cell Therapy Research Network (CCTRN) Biorepository Core Laboratory Rationale 
American heart journal  2011;162(6):973-980.
Moderate improvements in cardiac performance have been reported in some clinical settings after delivery of bone marrow mononuclear cells to patients with cardiovascular disease (CVD). However, mechanistic insights into how these cells impact outcomes are lacking. To address this, the NHLBI Cardiovascular Cell Therapy Research Network (CCTRN) established a Biorepository Core for extensive phenotyping and cell function studies, and storing bone marrow and peripheral blood for 10 years. Analyzing cell populations and cell function in the context of clinical parameters and clinical outcomes, after cell or placebo treatment, empower the development of novel diagnostic and prognostics. Developing such biomarkers that define the safety and efficacy of cell therapy is a major Biorepository aim.
doi:10.1016/j.ahj.2011.05.024
PMCID: PMC3236502  PMID: 22137069
5.  Cell Therapy and Satellite Centers: The Cardiovascular Cell Therapy Research Network Experience 
Contemporary clinical trials  2011;32(6):841-847.
Due to the changing population in patients with myocardial infarction, recruiting patients in clinical trials continues to challenge clinical investigators. The Cardiovascular Cell Therapy Research Network (CCTRN) chose to expand the reach and power of its recruitment effort by incorporating both referral and treatment satellite centers. Eight treatment satellites were successfully identified and they screened patients over a two year period. The result of this effort was an increase in recruitment, with these treatment satellites contributing 30 percent of the patients to two of the three Network studies. The hurdles these satellite treatment centers faced and how they surmounted them provide instruction to clinical research groups eager to expand to satellite systems and to health care practitioners who are interested in taking part in multicenter clinical trials.
doi:10.1016/j.cct.2011.07.001
PMCID: PMC3202446  PMID: 21767663
satellite centers; management; referral; recruitment
6.  Oversight and Management of a Cell Therapy Clinical Trial Network: Experience and Lessons Learned 
Contemporary clinical trials  2011;32(5):614-619.
The Cardiovascular Cell Therapy Research Network (CCTRN), sponsored by the National Heart, Lung, and Blood Institute (NHLBI), was established to develop, coordinate, and conduct multiple collaborative protocols testing the effects of cell therapy on cardiovascular diseases. The Network was born into a difficult political and ethical climate created by the recent removal of a dozen drugs from the US formulary and the temporary halting of 27 gene therapy trials due to safety concerns. This article describes the Network's challenges as it initiated three protocols in a polarized cultural atmosphere at a time when oversight bodies were positioning themselves for the tightest vigilance of promising new therapies. Effective strategies involving ongoing education, open communication, and relationship building with the oversight community are discussed.
doi:10.1016/j.cct.2011.05.003
PMCID: PMC3157886  PMID: 21616173
cell therapy; clinical trial network; institutional review boards; data safety and monitoring boards
7.  Combining Censored and Uncensored Data in a U-Statistic: Design and Sample Size Implications for Cell Therapy Research 
The assumptions that anchor large clinical trials are rooted in smaller, Phase II studies. In addition to specifying the target population, intervention delivery, and patient follow-up duration, physician-scientists who design these Phase II studies must select the appropriate response variables (endpoints). However, endpoint measures can be problematic. If the endpoint assesses the change in a continuous measure over time, then the occurrence of an intervening significant clinical event (SCE), such as death, can preclude the follow-up measurement. Finally, the ideal continuous endpoint measurement may be contraindicated in a fraction of the study patients, a change that requires a less precise substitution in this subset of participants.
A score function that is based on the U-statistic can address these issues of 1) intercurrent SCE's and 2) response variable ascertainments that use different measurements of different precision. The scoring statistic is easy to apply, clinically relevant, and provides flexibility for the investigators' prospective design decisions. Sample size and power formulations for this statistic are provided as functions of clinical event rates and effect size estimates that are easy for investigators to identify and discuss. Examples are provided from current cardiovascular cell therapy research.
doi:10.2202/1557-4679.1286
PMCID: PMC3154087  PMID: 21841940
U-statistic; clinical trials; score function; stem cells
8.  Rationale and Design for the Intramyocardial Injection of Autologous Bone Marrow Mononuclear Cells for Patients with Chronic Ischemic Heart Disease and Left Ventricular Dysfunction Trial (FOCUS) 
American heart journal  2010;160(2):215-223.
Background
The increasing worldwide prevalence of coronary artery disease (CAD) continues to challenge the medical community. Management options include medical and revascularization therapy. Despite advances in these methods, CAD is a leading cause of recurrent ischemia and heart failure, posing significant morbidity and mortality risks along with increasing health costs in a large patient population worldwide.
Trial Design
The Cardiovascular Cell Therapy Research Network (CCTRN) was established by the National Institutes of Health to investigate the role of cell therapy in the treatment of chronic cardiovascular disease. FOCUS is a CCTRN-designed randomized Phase II, placebo-controlled clinical trial that will assess the effect of autologous bone marrow mononuclear cells delivered transendocardially to patients with left ventricular (LV) dysfunction and symptomatic heart failure or angina. All patients need to have limiting ischemia by reversible ischemia on SPECT assessment.
Results
After thoughtful consideration of both statistical and clinical principles, we will recruit 87 patients (58 cell treated and 29 placebo) to receive either bone marrow–derived stem cells or placebo. Myocardial perfusion, LV contractile performance, and maximal oxygen consumption are the primary outcome measures.
Conclusions
The designed clinical trial will provide a sound assessment of the effect of autologous bone marrow mononuclear cells in improving blood flow and contractile function of the heart. The target population is patients with CAD and LV dysfunction with limiting angina or symptomatic heat failure. Patient safety is a central concern of the CCTRN, and patients will be followed for at least 5 years.
doi:10.1016/j.ahj.2010.03.029
PMCID: PMC2921924  PMID: 20691824
9.  Kids Identifying and Defeating Stroke (KIDS): Development and Implementation of a Multi-Ethnic Health Education Intervention to Increase Stroke Awareness Among Middle School Students and Their Parents 
Health promotion practice  2008;11(1):95-103.
The KIDS (Kids Identifying and Defeating Stroke) Program is a three-year prospective, randomized, controlled, multiethnic school-based intervention study. Program goals include increasing knowledge of stroke signs and treatment and intention to immediately call 911 among Mexican American (MA) and non-Hispanic white (NHW) middle school students and their parents. This article describes the design, implementation and interim evaluation of this theory-based intervention. Intervention students received a culturally appropriate stroke education program divided into four 50-minute classes each year during the 6th, 7th, and 8th grades. Each class session also included a homework assignment that involved the students’ parents or other adult partners. Interim-test results indicate that this educational intervention was successful in improving students’ stroke symptom and treatment knowledge and intent to call 911 upon witnessing a stroke compared with controls (p<0.001). We conclude that this school-based educational intervention to reduce delay time to hospital arrival for stroke shows early promise.
doi:10.1177/1524839907309867
PMCID: PMC2799540  PMID: 18332150
stroke; health disparities; Mexican Americans; social cognitive theory; school-based program
10.  Development of a Network to Test Strategies in Cardiovascular Cell Delivery: The NHLBI-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) 
The emerging sciences of stem cell biology and cellular plasticity have led to the development of cell-based therapies for advanced human disease. Pre-clinical studies which defined the potential of bone marrow-derived mononuclear cells to repair damaged and dysfunctional myocardium led to the rapid advancement of these strategies to the clinic. Such rapid advancement has led to controversy regarding the appropriate conduct of such studies. In the United States, the National Heart, Lung, and Blood Institute established the Cardiovascular Cell Therapy Research Network (CCTRN) to facilitate the early translation of clinical trials of cell therapy for left ventricular dysfunction. The premise upon which the CCTRN was established was that multiple clinical trial sites would interact effectively with a Data Coordinating Center to perform early phase 1 and 2 clinical trials within a highly coordinated network structure. In order to develop this network, the unmet needs of the community needed to be defined, the clinical trials identified, and the structure to perform the studies needed to be established. This manuscript highlights the challenges in the development of the CCTRN and the approaches faced to define a network to perform clinical trials in human cell therapy of cardiovascular disease.
doi:10.1007/s12265-009-9160-3
PMCID: PMC2863075  PMID: 20445812
Network; Cell Therapy; Biorepository; Management; Multicenter
11.  A study to assess the effects of a broad-spectrum immune modulatory therapy on mortality and morbidity in patients with chronic heart failure: The ACCLAIM trial rationale and design 
BACKGROUND:
Evidence has accumulated regarding the importance of inflammatory mediators in the development and progression of heart failure (HF). Although targeted anticytokine treatment strategies, specifically antitumour necrosis factor-alpha, have yielded disappointing results, this may simply reflect the redundancy of the cytokine cascade and the fact that antitumour necrosis factor-alpha therapies do not stimulate increased activity of the anti-inflammatory arm of the immune system.
Ex vivo exposure of autologous blood to controlled oxidative stress and subsequent intramuscular administration is a device-based procedure shown in experimental studies to have a broad-spectrum effect on a number of immune mediators. These studies have demonstrated that this approach downregulates inflammatory cytokines, whereas several anti-inflammatory cytokines are increased. In a feasibility study of 73 patients with moderate to severe HF, active therapy (versus placebo) had a significant benefit on both mortality and hospitalization, and was not associated with adverse hemodynamic or metabolic effects.
METHODS:
The Advanced Chronic heart failure CLinical Assessment of Immune Modulation therapy (ACCLAIM) trial is a multicentre, randomized, double-blind, placebo-controlled clinical trial of New York Heart Association functional class II to IV chronic HF patients with left ventricular ejection fraction of 30% or less. Enrolling approximately 2400 subjects at 177 sites, the primary end point of the study was the cumulative incidence (time to first event) of the combined end point of total mortality or hospitalization for cardiovascular causes. The study was completed in late 2005, when 701 primary end point events had occurred and all patients had been treated for six months.
CONCLUSIONS:
If the ACCLAIM trial confirms earlier results, this approach represents a novel nonpharmacological treatment for HF that targets a pathogenic mechanism contributing to progression of this syndrome not addressed by current therapies.
PMCID: PMC2649187  PMID: 17440642
Heart failure; Immune modulation; Ventricular dysfunction
12.  Excess Stroke in Mexican Americans Compared with Non-Hispanic Whites: The Brain Attack Surveillance in Corpus Christi Project 
American journal of epidemiology  2004;160(4):376-383.
Mexican Americans are the largest subgroup of Hispanics, the largest minority population in the United States. Stroke is the leading cause of disability and third leading cause of death. The authors compared stroke incidence among Mexican Americans and non-Hispanic Whites in a population-based study. Stroke cases were ascertained in Nueces County, Texas, utilizing concomitant active and passive surveillance. Cases were validated on the basis of source documentation by board-certified neurologists masked to subjects’ ethnicity. From January 2000 to December 2002, 2,350 cerebrovascular events occurred. Of the completed strokes, 53% were in Mexican Americans. The crude cumulative incidence was 168/10,000 in Mexican Americans and 136/ 10,000 in non-Hispanic Whites. Mexican Americans had a higher cumulative incidence for ischemic stroke (ages 45–59 years: risk ratio = 2.04, 95% confidence interval: 1.55, 2.69; ages 60–74 years: risk ratio = 1.58, 95% confidence interval: 1.31, 1.91; ages ≥75 years: risk ratio = 1.12, 95% confidence interval: 0.94, 1.32). Intracerebral hemorrhage was more common in Mexican Americans (age-adjusted risk ratio = 1.63, 95% confidence interval: 1.24, 2.16). The subarachnoid hemorrhage age-adjusted risk ratio was 1.57 (95% confidence interval: 0.86, 2.89). Mexican Americans experience a substantially greater ischemic stroke and intracerebral hemorrhage incidence compared with non-Hispanic Whites. As the Mexican-American population grows and ages, measures to target this population for stroke prevention are critical.
doi:10.1093/aje/kwh225
PMCID: PMC1524675  PMID: 15286023
cerebral hemorrhage; cerebrovascular accident; ethnic groups; Hispanic Americans; ischemic attack; transient; Mexican Americans; population surveillance; subarachnoid hemorrhage; BASIC, Brain Attack Surveillance in Corpus Christi
14.  Effect of Two Cancer Chemotherapeutic Agents on the Antibacterial Activity of Three Antimicrobial Agents 
Cancer chemotherapeutic agents and antibacterial antibiotics are often given concomitantly. Daunorubicin, cytosine arabinoside, and three antibiotics (gentamicin, amikacin, and ticarcillin) were tested individually and in combinations to determine their antimicrobial activity against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. These cytotoxic agents are commonly employed in the therapy of acute nonlymphocytic leukemia for remission induction therapy, and these antimicrobial agents are used in infection therapy. The maximum concentrations of the two cytotoxic drugs were chosen to be twice the known peak plasma levels of commonly employed dosage schedules. Neither of the cancer chemotherapeutic agents, alone or in combination, demonstrated bactericidal activity at the levels tested. However, in the presence of these agents, the antimicrobial activity of gentamicin and amikacin, although not that of ticarcillin, was depressed for 11 of 15 K. pneumoniae strains and 8 of 15 P. aeruginosa strains, but for none of the strains of E. coli. This level of decreased activity occasionally resulted in a minimal inhibitory concentration of the tested aminoglycoside well above the standard serum levels. Daunorubicin was more likely to antagonize gentamicin than was cytosine arabinoside.
PMCID: PMC352543  PMID: 103494

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