Author + information
- Received April 20, 2016
- Revision received April 27, 2016
- Accepted May 2, 2016
- Published online August 8, 2016.
- Thomas J. Povsic, MD, PhDa,∗ (, )
- Timothy D. Henry, MDb,
- Jay H. Traverse, MDc,
- F. David Fortuind,
- Gary L. Schaer, MDe,
- Dean J. Kereiakes, MDf,
- Richard A. Schatz, MDg,
- Andreas M. Zeiher, MDh,
- Christopher J. White, MDi,
- Duncan J. Stewart, MDj,
- E. Marc Jolicoeur, MDk,
- Theodore Bass, MDl,
- David A. Henderson, MDm,
- Patricia Dignacco, BSMTa,
- Ziangoiong Gu, MSa,
- Hussein R. Al-Khalidi, PhDa,
- Candice Junge, PhDn,
- Adel Nada, MD, MS, MFPMo,
- Andrea S. Hunt, MBAp,
- Douglas W. Losordo, MDq,
- RENEW Investigators
- aDuke Clinical Research Institute, Duke Medicine, Durham, North Carolina
- bCedars-Sinai Heart Institute, Los Angeles, California
- cMinneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, Minnesota
- dMayo Clinic Hospital, Phoenix, Arizona
- eRush University Medical Center, Chicago, Illinois
- fThe Christ Hospital Heart and Vascular Center, Cincinnati, Ohio
- gScripps Clinic Torrey Pines, La Jolla, California
- hDepartment of Medicine, University of Frankfurt, Frankfurt, Germany
- iOchsner Medical Center, New Orleans, Louisiana
- jOttawa Hospital Research Institute, University of Ottawa, Quebec, Ontario, Canada
- kMontreal Heart Institute, Université de Montréal, Montréal, Quebec, Canada
- lUniversity of Florida, Jacksonville Cardiovascular Center Jacksonville, Florida
- mCardiology Research Associates, Daytona Beach, Florida
- nAmgen Inc. Thousand Oaks, California
- oIntellia Therapeutics, Inc., Cambridge, Massachusetts
- pBaxalta US Inc., Bannockburn, Illinois
- qCaladrius Biosciences, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Thomas J. Povsic, Duke Clinical Research Institute, Duke Medicine, Box 103208, Duke University Medical Center, Durham, North Carolina 27708.
Objectives This study tested whether intramyocardial (IM) administration of mobilized, purified autologous CD34+ cells would improve total exercise time (TET) and angina frequency in patients with refractory angina.
Background IM administration of autologous CD34+ cells has been associated consistently with improvements in functional capacity and angina symptoms in early phase clinical trials.
Methods RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) was a randomized, double-blind, multicenter trial comparing IM CD34+ administration with no intervention (open-label standard of care) or IM placebo injections (active control). The primary efficacy endpoint was change in TET at 12 months. Key secondary endpoints include changes in angina frequency at 3, 6, and 12 months, and TET at 3 and 6 months. The key safety analysis was the incidence of major adverse cardiovascular events through 24 months.
Results The sponsor terminated the study for strategic considerations after enrollment of 112 of planned 444 patients. The difference in TET between patients treated with cell therapy versus placebo was 61.0 s at 3 months (95% confidence interval (CI): -2.9 to 124.8; p = 0.06), 46.2 s at 6 months (95% CI: -28.0 to 120.4; p = 0.22), and 36.6 s at 12 months (95% CI: -56.1 to 129.2; p = 0.43); angina frequency was improved at 6 months (relative risk: 0.63; p = 0.05). Autologous CD34+ cell therapy seemed to be safe compared with both open-label standard of care and active control (major adverse cardiovascular events 67.9% [standard of care], 42.9% (active control), 46.0% [CD34+]).
Conclusions Due to early termination, RENEW was an incomplete experiment; however, the results were consistent with observations from earlier phase studies. These findings underscore the need for a definitive trial. (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina [RENEW]: NCT01508910)
Despite improvements in revascularization techniques, there is a growing population of patients with chronic angina not amenable to further revascularization that suffers with severely limiting symptoms. Recent studies suggest that 5% to 15% of patients undergoing cardiac catheterization have significant disease not amenable to revascularization (1,2). These patients suffer from poor perceived health status and psychological distress (3), have significant impairments in quality of life (4), and represent a burden to the health care system due to significant resource use (5,6). Ranolazine and enhanced external counterpulsation are the only contemporary therapies developed for the treatment of this condition; however, recent studies have highlighted the limitations with ranolazine (7) and enhanced external counterpulsation has been associated with minimal reduction in angina (8).
Based on pre-clinical and early clinical studies, cellular therapies represent a theoretically attractive approach to the treatment of these patients (9–11). Autologous CD34+ cells may be a particularly potent cellular product, given their angiogenic capabilities (12). Pre-clinical models have established the superiority of isolated CD34+ cells over unselected bone marrow mononuclear cells in restoring microvascular circulation and improving tissue perfusion (12–14). In phase I and II double-blind, placebo-controlled clinical trials, intramyocardial (IM) administration of autologous CD34+ cells was associated with improvements in both angina frequency and exercise capacity as well as with a trend toward a reduction in the rates of major adverse cardiovascular events (MACE) (15–17). Four recent meta-analyses of early phase studies of cell therapy for chronic ischemic heart disease have further emphasized the possible effectiveness of this approach (18–21). To date, however, no single adequately powered trial has been performed to assess the efficacy and safety of a cellular therapeutic to treat refractory angina in patients lacking other treatment options.
We designed RENEW (Efficacy and Safety of Targeted Intramyocardial Delivery of Auto CD34+ Stem Cells for Improving Exercise Capacity in Subjects With Refractory Angina) as a pivotal phase III trial to determine whether IM delivery of purified autologous CD34+ cells would increase exercise capacity and decrease symptoms of angina in a refractory angina patient population (22). The trial was powered and designed with regulatory authorities to provide the requisite information for regulatory approval of the first cellular therapeutic for a cardiovascular indication.
The full rationale and design of the RENEW trial has been published elsewhere (22). RENEW was a randomized, double-blind, multicenter trial conducted at 45 centers in the United States (NCT01508910). An academic steering committee with sponsor representation helped to design the trial and was responsible for its conduct and for presentation and publication of the results. The trial was monitored by a data and safety monitoring board of independent physicians and a statistician with expertise in cardiovascular diseases and hematology; the data and safety monitoring board had access to unblinded data. The protocol was approved by appropriate regulatory and ethical boards at each site and conducted in compliance with the provisions of the Declaration of Helsinki. The trial was sponsored by Baxter Healthcare (Deerfield, Illinois).
Patients were eligible for the study if they were between 18 and 80 years of age; had Canadian Cardiovascular Society class III or IV angina; an ejection fraction of ≥25%; reproducible (within 20%) exercise-limiting angina (between 3 and 10 minutes on 2 consecutive modified Bruce protocol exercise treadmill tests [ETT]); reported a minimum of 7 angina episodes per week during a 4-week screening period; were on maximally tolerated medical therapy including β-blockers, calcium channel blockers, nitrates, and ranolazine; and had demonstrable ischemia on stress testing. Angiograms for each patient were reviewed by an independent committee composed of interventional cardiologists and surgeons to exclude need and eligibility for revascularization. Patients were ineligible if they were hospitalized for a cardiovascular indication or underwent percutaneous coronary intervention within 60 days, or underwent coronary artery bypass grafting or cardiac resynchronization therapy within 6 months. All patients provided written informed consent before undergoing any study-related procedures.
Using an interactive voice response system, patients were randomized in a 1:1:2 ratio, stratified by history of congestive heart failure, to either open-label standard of care (SOC) without intervention, double-blinded active control (AC) (granulocyte colony stimulating factor [G-CSF] stem cell mobilization, apheresis, and IM placebo injection), or autologous CD34+ cell therapy (G-CSF stem cell mobilization, apheresis, and IM CD34+ cell injection).
Patients in the SOC group received no intervention or further efficacy assessments (ETT, angina counts). All patients underwent follow-up visits for safety assessments at the same intervals as blinded patients.
All blinded patients underwent cell mobilization with G-CSF (5 μg/kg subcutaneously) for 4 days followed by apheresis on day 5. The mobilized peripheral cell product was shipped to a central processing facility (Progenitor Cell Therapy, Allendale, New Jersey, or Mountain View, California) for selection of CD34+ cells using an ISOLEX 300i system (Baxter Healthcare Corporation). If the product did not meet release criteria, placebo was substituted at the processing center, and the patient was injected; the patient and investigator remained blinded. Within 96 hours of apheresis, all blinded patients underwent left ventricular endocardial mapping using the NOGA XP endocardial mapping system followed by injection (10 × 0.2 ml) of 1 × 105 auto-CD34+ cell/kg up to 1 × 107 cells or matching placebo, using the MyoStar catheter (Biosense Webster, Diamond Bar, California). Limited echocardiography was performed for pericardial effusion after the procedure (<4 h).
Patients in whom injections could not be completed in a blinded fashion, and were thereby unblinded, had all follow-up data imputed as the last observation carried forward.
Clinical assessments were performed at 2 and 5 weeks, and 3, 6, 12, 18, and 24 months from randomization. Patients were contacted by phone monthly to ensure rapid and complete endpoint assessment. Assessment of exercise capacity using ETT was performed at 3, 6, and 12 months in blinded AC and CD34+ patients. Angina counts were recorded using an electronic diary for 28 days before these visits.
The primary efficacy endpoint was a change from baseline in total exercise time (TET) measured using a modified Bruce protocol through 12 months. After review of the angina diaries and before unblinding, it was noted that some patients had failed to record a lack of angina in the electronic angina diaries; therefore, a decision was made before database lock to uniformly impute no entry of angina as a lack of angina. The principal safety endpoint was the incidence of MACE including all-cause death, myocardial infarction, stroke, or cardiovascular hospitalization through 24 months, as adjudicated by an independent clinical events committee whose members were unaware of study treatment (Duke Clinical Research Institute, Durham, North Carolina). Secondary endpoints included change in TET at 3 and 6 months and change in angina frequency at 3, 6, and 12 months.
The primary efficacy analysis was based on the intention-to-treat (ITT) population, consisting of all randomized patients analyzed according to their random allocation. A change from baseline analysis of covariance with repeated measures on the ITT data was performed using a mixed-effects model. The independent parameters in the model will be treatment group and visit (3, 6, and 12 months) and the interaction between treatment group and visit. The individual baseline values were used as a covariate. The baseline value of TET was the average of the 2 TETs measured during the screening period.
Analysis of angina frequency was performed using a log linear model (Poisson regression with extra variability, overdispersed) with repeated measures on the frequency of angina at 3, 6, and 12 months. The independent parameters in the model were treatment group and visit (3, 6, and 12 months) and the interaction between treatment group and visit using the log of the baseline value as a covariate. Because this analysis is done on the log scale, these contrasts take the form of ratios. Because the angina diary could only record angina episodes occurring within a 1-day window of the time of the recording, a lack of reported angina during the reporting period was assumed to reflect an absence of angina on that day.
Secondary endpoints were to be evaluated using a hierarchical closed testing procedure to preserve overall type I error. SAS version 9.2 (SAS Institute, Inc., Cary, North Carolina) was used to perform all statistical analyses. A sensitivity analysis was prespecified using a per-protocol population, a subset of the ITT population of patients who underwent injections according to study product received. The rates of MACE were analyzed using the population of all patients as randomized as well as all patients as injected. Analysis of adverse events was stipulated as injected. Continuous variables are described as mean ± SD or as medians and interquartile ranges, as appropriate.
Given the premature termination of RENEW, the investigators recognize that formal efficacy evaluation of the therapy is no longer possible; thus, all comparisons are considered hypothesis generating only and no claims of efficacy or safety can be made.
Role of the funding source
The sponsor of the trial, Baxter Healthcare Corporation, participated in the design of the trial and protocol in collaboration with the steering committee. The sponsor was responsible for submission of the protocol for approval by national regulatory authorities, and data collection. Data analysis was performed at the Duke Clinical Research Institute. The corresponding author drafted this manuscript and made all revisions based on input from the coauthors.
We randomized 112 patients between April 17, 2012, and December 4, 2013. On December 4, 2013, the sponsor notified all sites that enrollment was being suspended due to strategic considerations and independent of any unblinded analysis. All patients in active screening were discontinued. Baseline characteristics are detailed in Table 1 and are reflective of an advanced refractory angina population—74% had Canadian Cardiovascular Society class III angina, 26% had Canadian Cardiovascular Society class IV angina, 57% had diabetes, 87% had previous coronary artery bypass grafting, and 91% had previous percutaneous coronary intervention. Patients were well-treated, with 96% on β-blockers, 85% on long acting nitrates, 42% calcium-channel blockers, and 60% on ranolazine.
Summary of exposure
Patient disposition is detailed in Figure 1 and Table 2. Of 297 patients consented, 112 were randomized, 28 (25.0%) to SOC, who underwent no study procedures. All patients randomized to AC (27 [24.1%]) or CD34+ therapy (57 [50.9%]) underwent G-CSF injections, and 83 (98.8%) completed the mobilization phase. Three patients randomized to CD34+ therapy underwent blinded placebo injections due to failure of cell processing before release of product. Six patients (2 AC, 4 CD34+ therapy) did not undergo injection of study product due to adverse events during cell procurement or mapping; thus, the per-protocol population included 50 patients undergoing CD34+ cell injection and 28 undergoing placebo injections.
Assessments of exercise times and change in exercise time from baseline at each time point in patients as randomized (Table 3) and as treated (Table 4) are presented. With assessment of only 112 of the planned 444 patients, RENEW was not powered sufficiently to demonstrate a significant difference in improvement in TET between the cell therapy and AC groups (difference between groups in the ITT populations: 42.1 s at 3 months [95% confidence interval (CI): -20.6 to 104.8; p = 0.19], 34.7 s at 6 months [95% CI: -37.7 to 107.0; p = 0.34], and 20.4 s at 12 months [95% CI: -68.9 to 109.6; p = 0.65]).
There was a significant placebo effect with marked increases in mean and median TET across all patients (Figure 2, analysis by ITT population shown in Online Figures 1A and 1B). Assessing patients according to therapy received, we observed an increase in exercise capacity from 419.1 ± 107.6 s to 506.1 ± 224.7 s at 12 months in placebo patients and from 413.2 ± 120.9 s to 537 ± 204.7 s in CD34+-treated patients. Changes in exercise time from baseline were 95 ± 151.2 s (6 months) and 86.9 ± 201.9 s (12 months) in placebo patients versus 141.5 ± 163 s (6 months) and 123.8 ± 192.4 s (12 months) in cell therapy patients. Similar improvements were observed in median exercise times of 84.5 s and 68.5 s, respectively, in placebo patients versus 132 s and 107 s in CD34+-treated patients.
Angina frequency was markedly reduced in both blinded randomized groups (Table 5). The mean number of angina episodes decreased from 13.9 ± 8.6 to 4.2 ± 5.4 at 6 months and to 2.7 ± 4.6 in control patients, whereas those randomized to cell therapy had a reduction from 19.1 ± 12.8 to 4.0 ± 6.1 at 6 months and 3.8 ± 6.2 at 12 months. Notably, the median number of reported angina episodes per week was 0.9 and 1.6 in the AC and cell therapy–treated groups, respectively. Controlling for differences in baseline angina frequency, the relative risk of angina was 0.58 (p = 0.02) and 0.63 (p = 0.05) at 6 months in the ITT and as-treated populations, respectively, and 1.02 (p = 0.95) and 0.95 (p = 0.87) at 12 months.
The incidence of MACE was highest in the open-label SOC group (Table 6). Death rates were low in all arms (7.1% SOC vs. 10.7% AC vs 4.0% CD34+ treatment). MACE rates were driven by the incidence of cardiovascular hospitalizations, with low mortality and incidence of myocardial infarction, and no strokes. There was no evidence that cell therapy was associated with an excess of ventricular arrhythmias. The occurrence of adverse events followed a similar pattern (Online Table 1).
Based on rigorous pre-clinical models (12–14) and 2 double-blind studies that demonstrated improvements in exercise capacity and symptoms of angina (15,16), RENEW was designed to definitively evaluate the safety and efficacy of IM injection of mobilized CD34+ cells for severely symptomatic and functionally disabled patients lacking medical or interventional options. After extensive discussions with regulatory authorities, RENEW was designed to meet regulatory requirements via a special protocol assessment, including incorporation of 2 control groups to establish the safety of procurement and IM injection of a cellular therapeutic and to determine if periprocedural events translated into longer term risk (22,23).
Comparison with prior trials
With less than one-quarter of the planned enrollment and, as terminated, smaller in scope than the phase II ACT-34 (Injection of Autologous CD34-Positive Cells for Critical Limb Ischemia) trial, RENEW is severely limited in any assessment of efficacy between cell therapy and AC; however, the results reflect those made in earlier phase studies.
Comparison with the results of ACT-34 is informative. First, RENEW showed large improvements in exercise times in placebo-treated patients, attesting both to effective blinding in the trial and supporting the known significant placebo effect in this highly symptomatic patient population. The placebo effect observed in our study (mean of approximately 90 s) is considerably larger than that observed in ACT-34 (58 ± 146 s) (15) or in other blinded trials in this field (24–28). Despite this, cell therapy–treated patients displayed greater exercise capacity at each time point. Cell therapy was associated with improvement in both mean and median TET of >2 min at 6 months, identical to the observations made in ACT-34 (15).
Cell therapy was also associated with numerical improvements in angina at both 3 and 6 months. Notably, placebo-treated patients recorded a median frequency of 0.9 angina episodes per week at the 12-month follow-up, representing a >90% decrease in angina frequency. The reason for this dramatic reduction in angina is unclear, and may represent a placebo effect and/or difficulty with recording angina episodes. We also cannot exclude that knowledge of trial termination impacted patient engagement and participation in the process of recording of angina episodes.
Consistent with previous trials, cell therapy seemed to be safe, with no increase in the risk of MACE in treated patients. A key concern in other trials has been whether procedures associated with cell procurement and administration, including cardiac perforation during IM delivery and infarction during cell mobilization, would offset any benefit from the therapy, manifesting as an increased risk of future untoward clinical events. The U.S. Food and Drug Administration mandated that RENEW include 2 control arms: an AC comparator to assess for safety signals related to the cell product, as well as an SOC arm to address overall procedural/cell safety. The use of an open-label SOC arm remains controversial in a population of highly symptomatic patients with limited options. We cannot know how or if the personal discouragement of being excluded from active participation may have influenced these patients. The rate of clinical events during the intervention period (defined as the 2 weeks from randomization/start of study procedures) was limited. More important, clinical events over the ensuing 2 years occurred most frequently in the SOC arm, emphasizing the benefit of participating in clinical trials in general, and demonstrating that autologous cell procurement and IM injection, although not risk free, does not lead to a higher risk of future events. Mortality remained numerically lower in patients treated with cell therapy, consistent with findings from ACT-34 and other cell therapy studies (21). Finally, the requirement of a SOC arm in RENEW was perceived as an impediment to enrollment, which may have contributed to the decision to halt the study by the sponsor. We believe these findings obviate the need for similar 3-arm designs in future studies and point to the limitation of this comparator.
Early study termination
Given the early termination of the study, RENEW stands as an incomplete experiment. Our findings are consistent with earlier studies enrolling identical patients with virtually identical comparison groups, each demonstrating improvements in both exercise capacity and angina frequency (15,16). Longer term follow-up from ACT-34 suggested that the improvement in angina frequency, as well as the lower risk of clinical events and mortality, might be sustained to 24 months (15,29).
Several meta-analyses are consistent with these observations (18–21). An assessment of 5 trials with 381 patients demonstrated a significant improvement in exercise time of 61 s, a lower incidence of the number of angina episodes, and lower risk of both myocardial infarction and death (21). A broader analysis including 9 trials enrolling patients with ischemic heart disease observed a significant decrease in mortality, angina class, and angina frequency (18). The most recent of these analyses encompassing 6 trials with 353 patients demonstrated significant improvements in exercise time, angina frequency, angina class, medication use, and perfusion imaging, as well as a decreased risk of MACE (19).
To date, however, no single trial has adequately assessed the impact of a cellular therapy on functional capacity. In this regard, the decision to terminate the study early represents a lost opportunity to define the efficacy of this therapy and perhaps to receive regulatory approval of the first cell therapeutic agent for cardiovascular disease.
The decision to terminate RENEW was based solely on strategic considerations. The ethics and appropriateness of premature cessation of clinical trials for business reasons has been much debated (30–35), and many have been strongly critical of commercial sponsors; however, strategic considerations are complex. The desire to have an agreement in place regarding regulatory requirements for this complex therapy before starting RENEW led to a 50-month delay between enrollment of the last patient in ACT-34 and the first patient in RENEW. Randomization was projected to continue into at least 2015, and the Food and Drug Administration had articulated their policy on requiring confirmation of results in independent studies. Each of these factors impacted the commercial viability of this therapy.
The role of “futility” in this regard is contentious. Completion of RENEW would have defined the effect of this therapy on exercise capacity and patient well-being, one of the goals of the trial, but may not have led to a commercially viable therapy given these timelines and intellectual property limitations that were known before trial commencement. Given that a key impetus to participation in trials such as RENEW is the development of therapies that would help similarly afflicted patients, the ethics of terminating enrollment if commercial considerations preclude this promise is unclear. Fortunately, the sponsor agreed to the steering committee’s insistence that all patients be followed as initially consented and all available data be analyzed and published.
The experience of RENEW illustrates the need for more efficient trials and pathways toward regulatory approval, especially for complex biologics/therapies such as cellular therapeutics for conditions such as refractory angina.
The primary limitation of RENEW is its premature termination—RENEW cannot assess for the presence or lack of efficacy or safety. In addition, the impact of early termination on patient and investigator participation and engagement is unknown; although notably, all patients alive underwent 12-month ETT assessments as specified.
Due to early termination, RENEW was underpowered to assess adequately the efficacy of IM administration of autologous CD34+ cells for the treatment of refractory angina. Our findings are consistent with other studies, which show provocative trends toward improvements in outcomes in CD34+ cell-treated patients, while adding to the significant body of evidence that IM cell therapy is safe. Our study calls into question the value of an SOC comparator. The usefulness of autologous CD34+ cell therapy for refractory angina for this highly symptomatic and limited patient population remains incompletely defined.
WHAT IS KNOWN? Early phase trials have suggested that intramyocardial administration of selected CD34+ stem cells results in improvements in exercise tolerance and decreased angina.
WHAT IS NEW? RENEW was designed to definitively evaluate the efficacy and safety of this approach, but was terminated prematurely by the sponsor due to strategic considerations. Although enrollment was only one-quarter of what was planned originally, the results of RENEW are consistent with prior studies, and suggest that auto-CD34+ cell therapy could represent an important addition to the armamentarium for treatment of these highly symptomatic patients without other treatment options.
WHAT IS NEXT? RENEW suggests that further resources should be harnessed to definitively assess the efficacy of stem cell approaches, especially with auto-CD34+ cells, for treatment of refractory angina.
For a list of adverse events and a complete list of members of the Data Safety Monitoring Board and trial investigators, please see the online version of this article.
The RENEW trial and this analysis were funded by Baxter Healthcare and Baxalta US Inc. Baxter Healthcare and Baxalta US Inc. provided the Duke Clinical Research Institute with funding for this research.
Drs. Povsic, Dignacco, Gu, and Al-Khalidi are employees of the Duke Clinical Research Institute.
Drs. Junge, Nada, and Losordo were employees of Baxter Healthcare during the conduct of this study.
Dr. Hunt is an employee of Baxalta US Inc.
Dr. Henry has received modest consulting fees from Baxter Healthcare.
Drs. Povsic and Henry contributed equally to this work.
- Abbreviations and Acronyms
- active control
- exercise treadmill tests
- granulocyte colony stimulating factor
- major adverse cardiovascular event(s)
- standard of care
- total exercise time
- Received April 20, 2016.
- Revision received April 27, 2016.
- Accepted May 2, 2016.
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