Expectations of Cell Therapy: An Evaluation of the Cardiovascular Cell Therapy Research Network PACE Trial

Clinical Researcher—May 2018 (Volume 32, Issue 5)


Shelly L. Sayre, MPH; Judy Bettencourt, MPH; Michelle Cohen, MPH; Rachel W. Vojvodic, MPH; Emerson C. Perin, MD, PhD; Phillip C. Yang, MD; Michael P. Murphy, MD; Doris A. Taylor, PhD; Patricia G’Sell, RN; Eileen Handberg, PhD; Lem Moyé, MD, PhD

[DOI: 10.14524/CR-17-0041]

[Editor’s Note: Tables and Figures associated with this article are available in a PDF in the library of the Clinical Trials Recruitment Interest Group of the ACRP Online Community.]


Clinical trials represent hopeful new therapies to many people. The majority of healthcare advances today are made possible by the willingness of individuals to take part in clinical trials.

There are many motivators for enrolling in clinical trials, including altruism, desire to play an active role in one’s own healthcare, and a desire to gain early access to novel treatments.{1,2} What one might expect from participating in a clinical trial can be influenced by multiple sources, (e.g., media coverage of new research, acquaintances who have had treatment, or advertisements instructing audiences to “ask your doctor” for this latest treatment option).{3,4}

However, with “new” often being equated with “better,” investigational treatments can be misconstrued as a panacea, generating unrealistic expectations even before a trial has begun. Expectations often run high in clinical trials that explore novel treatments for serious diseases.  For example, expectations are that stem cell therapy will have an impact in a number of applications, (e.g., cardiology,{5-7} traumatic brain injury,{8,9} Parkinson’s disease,{10} etc.). Accordingly, cell therapy has received increased media coverage over the last decade for both regulated and unregulated uses.{4,11-15}

Investigators are exploring how information about stem cell therapy (accurate or not) enacts the power of hope in both patients and caregivers.{16-18} Many for-profit clinics offer stem cells for a wide spectrum of diseases and make claims of success without regulated oversight, raising questions as to whether there is evidence of success or if findings are based solely on individuals’ expectations. A review of the literature identified no instrument to assess participant expectations for cell therapy clinical trials with regard to symptom relief, improved quality of life, and treatment efficacy.

This study evaluated participants’ self-reported expectations associated with enrollment in a clinical trial assessing the effect of stem cell therapy on intermittent claudication. The study also examined changes in participant expectations over time, and the relationship between their perceived treatment assignment and expectations.


The PACE Trial

The PACE trial (Patients with Intermittent Claudication Injected with ALDH Bright Cells) was a Phase II, double-blind, placebo-controlled, randomized trial conducted by the Cardiovascular Cell Therapy Research Network (CCTRN) and funded by the National Heart, Lung, and Blood Institute. The trial was designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells delivered to participants with atherosclerotic peripheral artery disease (PAD) with symptom-limited intermittent claudication. Intermittent claudication is pain and/or cramping in the lower leg during exercise (caused by reduced blood flow to the vessels) that is relieved by a short period of rest.

Following 1:1 randomization, 78 participants were treated with cells or placebo administered via direct intramuscular injection to the calf and lower thigh and followed for six months. Participation included eight visits over six months, with a total maximum time commitment of 31 hours. Visit ranged from one to six hours, with the longer visits at time of bone marrow harvest and those including endpoint collection activities (MRI and treadmill testing). The design and outcomes of the trial are further described elsewhere.{19,20}

The Participant Expectation Questionnaire

The Participant Expectation Questionnaire (PEQ) was developed by CCTRN research staff and administered to participants as a first attempt to learn more about their cell therapy expectations and participation in a clinical trial studying it. It has not been validated, and will require this step if it is to be used in future trials. As the PACE trial demonstrated neither beneficial nor harmful effect of cell therapy on the primary measures of peak walking time or increased blood flow in the affected leg,{20} all questionnaires were combined into one cohort for this evaluation.

The PEQ included categorical and open-ended response choices (see Table 1) and construct models used in similar evaluations of pain medicine.{21} Categorical responses used a Likert scale format to assess several aspects of expectation relating to trial participation. Topic areas included symptom relief, effectiveness of cell therapy, and trial participation. The open-ended portion focused on what might influence expectations and included motivation to participate, knowing someone who had received stem cells to treat a disease, discussion of the PACE trial with anyone before participating, and availability of any person(s) to help the participant during the study. The PEQ was administered prior to study injection (baseline) and was repeated at the six-month follow-up visit.

Statistical Methods

Text responses were independently coded by two coauthors using categories generated from the most common themes. Differences were adjudicated by a third coauthor. If participants gave more than one response, all were coded and included in analysis. For categorical data, frequency (counts and percentages) of responses to each item was tabulated. Comparisons of the distribution of response by perceived treatment assignment were carried out using Fisher’s exact test for dichotomous outcomes and chi-square statistics for the polychotomous responses. All computations were conducted using SAS 9.4. No corrections for multiplicity were employed in these exploratory analyses.


Seventy-eight participants were randomized and received study product in the PACE trial. These participants completed a PEQ at baseline and six months post-treatment, and are the basis for this investigation.

Motivation for Participation

More than half of the participants decided to take part in the trial the same day the consent was reviewed with them by the research team (n=41; 53%), with most (n=64; 82%) reportedly discussing the trial with someone beforehand (i.e., a family member or physician). Almost all participants (n=73; 94%) said they had someone to help them during participation.

Principal motivations for trial participation were to reduce pain and avoid invasive treatments (n=33; 44%) and to get better (n=24; 32%). Other motivating factors included helping others by participating (n=13; 17%), improving mobility/quality of life (n=10; 13%), and following physician recommendations (n=5; 7%). A small minority of participants (n=10; 13%) knew someone who had been treated with stem cells.

Expectations Over Time Regarding Symptom Relief

Fifty-three participants (68%) had a well-established PAD history, diagnosed greater than three years before study participation, with the remaining (n=24; 32%) diagnosed within two years of study participation. The study utilized the Rutherford classification system, which categorizes PAD symptoms into acute or chronic limb ischemia to direct treatment regimens. Nearly all trial participants were Rutherford classification 2 or 3 (indicating moderate to severe claudication).{20}

As shown in Table 2, at baseline, 66 participants (85%) felt that stem cells would make them feel better in general. Sixty participants (77%) had a high expectation for either a large reduction or elimination of leg pain, and 51 participants (65%) agreed/strongly agreed that they would be able to walk without pain post-treatment.

At six months post-treatment however, 28 participants (36%) felt that stem cells made them feel better in general. Similarly, 28 participants (36%) reported their leg pain remained the same, and only 11 (14%) agreed/strongly agreed that they walked without pain after study treatment.

Expectations Over Time for Treatment of Disease

At baseline, 65 participants (83%) had high expectations for the effectiveness of stem cells at treating disease, despite the fact (noted above) that most did not know anyone personally who had received them. At six months post-treatment, 49 participants (63%) still agreed/strongly agreed that stem cells were effective at treating disease (see Table 2).

Expectations Over Time Related to Trial Participation

At baseline, 67 participants (86%) felt that taking part in the study would be easy; however, 59 participants (76%) expected some minor inconveniences and 25 (32%) anticipated being tired due to logistical complications of participation (see Table 2). At six months post-treatment, 72 participants (92%) agreed/strongly agreed that it was easy to participate, with 17 participants (22%) indicating minor inconveniences and 13 (17%) reporting feeling tired due to logistical complications.

Dislikes, Likes, and Future Expectations

When asked about dislikes regarding study treatment (see Figure 1a), 34% of the respondents indicated “none.” Respondents citing specific concerns primarily mentioned the magnetic resonance imaging scan and blood draws/needle use. When asked what they liked about study treatment (see Figure 1b), respondents mentioned the study team and seeing results or feeling better after treatment. In the end, the majority (90%) indicated a willingness to participate in another stem cell study.

Perceived Treatment Assignment

When the participants were asked which treatment they thought they had received, 26 participants (33%) indicated cells, 22 (28%) indicated placebo, and 30 (39%) reported they “did not know.” A clear majority of participants, 48 (61%) felt they could identify with being in either the cell or placebo group.

A subgroup exploration of the latter 48 individuals was conducted to assess differences. As shown in Table 3, the two perceived treatment groups were not significantly different in their expectations at baseline. Both groups expected a large reduction or elimination of leg pain (cells n=21, 81% vs. placebo n=18, 82%); to be able to walk without pain (cells n=19, 73% vs. placebo n=16, 73%); to feel better in general due to the stem cells (cells n=20, 77% vs. placebo n=21, 95%); and that stem cells are effective for treating disease (cells n=20, 77% vs. placebo n=19, 86%). Similar to the overall study cohort, both groups thought it would be easy to participate in the study (cells n=21, 81% vs. placebo n=19, 86%), though some recognized the potential for minor inconveniences (cells n=19, 73% vs. placebo n=17, 77%).

At six months post-treatment (see Table 3), differences between the two groups emerged—particularly for symptom relief. While only two (8%) cell-perceived participants felt their leg pain stayed the same, 13 placebo-perceived participants (59%) reported their pain remained the same (p<0.001). When asked about the ability to walk without pain, 10 cell-perceived participants (38%) agreed/strongly agreed while none in the placebo-perceived group agreed (p<0.001). The two groups also differed drastically on the idea that, in general, stem cells made them feel better (cell n=21, 81% vs. placebo n=2, 9%, p<0.001).

While the two perceived treatment groups differed on symptom relief at six months post-treatment, there were no significant differences related to effectiveness of treatment or trial participation. Both groups agreed that stem cells were effective for treating disease (cell n=20, 77% vs. placebo n=15, 68%); that it was easy to participate in the study (cell n=24, 92% vs. placebo n=20, 91%); and that they experienced only minor inconveniences (cell n=9, 35% vs. placebo n=6, 27%) (see Table 3). Overwhelmingly, members of both groups reported they would participate in another stem cell study (cell n=24, 92% vs. placebo n=21, 95%).

The same analysis was repeated utilizing the 48 participants’ actual treatment assignments. There was no significant effect of actual treatment assignment on expectations at either baseline or at six months post-treatment.

The Interrelationship of Perceived Assignment and Actual Assignment

In order to assess the impact of actual therapy assignment on the relationship between perceived therapy and expectation variables, the analyses were repeated within each of the actual cell and placebo groups. In the subgroup of 48 participants, 24 were assigned to cells and 24 assigned to placebo.

At six months post-treatment, among those in the actual cell group, participants who perceived they received cells experienced statistically significant differences in leg pain reduction (p<0.001), walking without pain (p=0.005), and feeling better overall (p<0.001) compared to those who perceived they received placebo (see Table 4). Results at six months post-treatment in the actual placebo group showed that perceived therapy was only significantly associated with generally feeling better due to stem cells (p=0.047).


In the PACE trial, participants’ motivations were largely driven by their desire for symptom reduction and overall improved feeling. Post-treatment, only 14% of participants agreed/strongly agreed they could walk without pain; however, 36% still agreed/strongly agreed that stem cells made them feel better in general. There was a 20% decrease in expectation fulfillment from the beginning of the trial to the end in the effectiveness of stem cells; a number that is not surprising in a trial that demonstrated neither beneficial nor harmful effects of cell therapy on its primary endpoints.

Most participants made the decision to participate in the trial the same day the consent form was reviewed, suggesting that much of the prior information they had was sufficient for them to feel comfortable to proceed. It is clear, however, that following the intervention, participants began to develop their own beliefs about their treatment conditions. Participants who ventured a guess were correct nearly half the time (n=22; 46%).

Since participants in a trial frequently try to guess their treatment assignment, we felt it was an important factor (beyond the control of the investigators) to explore, as these “impressions” can alter a participant’s compliance with attendance or influence adverse event reporting. Members of both the cell-perceived and placebo-perceived groups continued to respond favorably to the effectiveness of stem cells at treating their disease in the post-treatment period. They also responded similarly on questions related to trial participation and logistics; however, it is notable that those who perceived they received cells were more likely to report reduction in leg pain and feeling better overall than those who perceived they received placebo (85% vs. 18%).

Most striking is that 77% in the cell-perceived group also indicated their leg pain decreased compared to only 9% of the placebo-perceived group. Even though the vast majority of participants in either group were still experiencing pain when walking, nearly all indicated they would participate in another stem cell study.

In the perceived therapy versus actual therapy subgroup evaluation, perceived therapy produced a greater impact on expectations than actual therapy. This is to be expected, since one of the purposes of randomization is the equal distribution of expectations across treatment groups. However, the impact of perception appeared greater in those who actually received the cells. Thus, although perceptions were distributed equally across the cell and placebo groups, the relationship between expectations and outcomes was much stronger in participants receiving cells.

The equal distribution of perception across the randomized groups mitigates against unintentional unblinding of the actual group assignment to the participants. Despite these protective measures, there are likely subjective factors that may affect participants’ perceptions of their own outcomes and feelings after study intervention has occurred. Post-intervention expectations (e.g., placebo effect){22,23} may present a greater challenge in that they are intrinsic to the subject. This observation is the most intriguing of the findings and warrants further investigation.


Although validation of the PEQ is warranted for future use, responses to the survey revealed that several factors shape the expectations of participants prior to considering a cell therapy trial. On evaluation at six months post-treatment, the inclusion of a “don’t know” option for perceived treatment assignment prevented full sample evaluation of the influence of perception on expectations. No interim assessments were collected between baseline and six months post-treatment to allow identification of any changes in the trajectory of participant expectations.

Since perception was asked only at six months post-treatment, one can question whether the perception of therapy induced the change in expectations or if the change in expectations affected the perception. Lastly, this investigation is limited to one trial of one cell type and its effect on one disease process, and it is not intended to be generalized.

As the field of cell therapy continues to expand, it will be important to know how expectations change with accumulated, reported experiences (both positive and negative) of many different types of stems cells in the treatment of different disease processes.


Patients are often not vocal with their physicians about expectations regarding their treatment, nor about possible logistical hurdles which threaten to hinder their clinical trial participation. The PEQ findings demonstrate high initial expectations were moderated over time, and perhaps even influenced by perceived treatment assignment, although the perception-response relationship in the cell group requires additional investigation.

Despite this, enthusiasm for the effectiveness of the treatment and participation in future trials remained. Eliciting and understanding participant expectations prior to enrollment in a stem cell therapy trial may help investigators have a more targeted conversation with potential participants. This discussion allows an opportunity to explain possible outcomes in realistic terms, benefiting both the trial and participants.


We wish to thank Lynette Westbrook, RN, MS, CCRC, and Rachel Olson, RN, MS, MBA, CCRC, for their assistance in development of the PEQ for use in the PACE trial.

In memory of our dear friend and colleague, Alan T. Hirsch, MD, we share these findings with the community in the hopes it will foster continued conversation between physicians and patients about the critical role of research in healthcare.


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Shelly L. Sayre, MPH, (shelly.l.sayre@uth.tmc.edu) is at the University of Texas (UT) Health School of Public Health.

Judy Bettencourt, MPH, (judith.l.bettencourt@uth.tmc.edu) is at the UT Health School of Public Health.

Michelle Cohen, MPH, is at the UT Health School of Public Health.

Rachel W. Vojvodic, MPH, is at the UT Health School of Public Health.

Emerson C. Perin, MD, PhD, is at the Texas Heart Institute.

Phillip C. Yang, MD, is at the Stanford University School of Medicine.

Michael P. Murphy, MD, is at the Indiana University School of Medicine.

Doris A. Taylor, PhD, is at the Texas Heart Institute.

Patricia G’Sell, RN, is at the Indiana University School of Medicine.

Eileen Handberg, PhD, is at the University of Florida School of Medicine.

Lem Moyé, MD, PhD, (lemmoye@msn.com) is at the UT Health School of Public Health.