About the CONCERT-HF study
The CONCERT-HF study, funded by the National Heart, Lung, and Blood Institute (NHLBI), part of the NIH, launched in 2015. This study sought to determine whether c-kit+ cardiac cells (CPCs), either alone or in combination with mesenchymal stromal cells (MSCs) derived from bone marrow, were safe for and beneficial to people who have chronic heart failure. Despite significant medical and surgical advances, people who have chronic heart failure have very limited treatment options. As a result, they continue to experience a low quality of life, and about half will die within five years of receiving a diagnosis.
AT A GLANCE
- Participants in the CONCERT-HF study were randomly selected to receive one of four treatments: CPCs and MSCs together, CPCs alone, MSCs alone, or placebo.
- Tests performed during these visits determined how the treatments may have affected the participant’s health and their heart’s ability to pump blood.
- Results from the CONCERT-HF trial showed that cell-based therapy can be safe and feasible for people with chronic heart failure.
- Researchers reported lower rates of death and hospitalization, and improved quality of life, for some participants.
CONCERT-HF study design
CONCERT-HF was the first multi-center, randomized, double-blind, placebo-controlled trial evaluating CPCs and the combination of two cell types (CPCs and MSCs) from different tissues in ischemic heart failure patients. Participants were randomly selected to receive one of four treatments: CPCs and MSCs together, CPCs alone, MSCs alone, or placebo.
Participants had tissue samples collected from their heart and bone marrow to prepare the cell-based products. One of these products or a placebo was injected directly into each participant’s heart via a catheter. Each participant then had regular follow-up visits—after one day, one week, one month, three months, six months, and 12 months. Tests performed during these visits determined how the treatments may have affected the participant’s health and their heart’s ability to pump blood.
CONCERT-HF study results
Relative to the placebo group, study participants showed some clinical benefit in major adverse cardiac events (MACE) and quality of life (QOL) from CPCs or MSCs, respectively. Participants receiving the combination of MSCs and CPCs also showed improvements for both MACE and QOL relative to placebo-treated participants. These positive results were not accompanied by changes in left ventricular function or cardiac structure, suggesting that the effects may have been mediated by systemic or paracrine mechanisms. Taken together, the CONCERT-HF trial disclosed potentially important beneficial effects of CPCs and MSCs, either alone or in combination.
Following is a more detailed summary of the CONCERT-HF study results:
- The treatments were shown to be safe and feasible;
- The proportion of MACE was significantly decreased (from 28% to 6.5%) in the CPCs alone group (P = 0.043). A similar but nonsignificant decrease (from 28% to 9.1%) was observed in the MSCs+CPCs combination group (P= 0.061);
- QOL (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs+CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volume, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among the four groups;
- No significant effects on the heart’s structure or function were observed in any of the four groups.
The CONCERT-HF results were published in The European Journal of Heart Failure on April 3, 2021, and are summarized at ClinicalTrials.gov.
CONCERT-HF study history
Calls for the retraction of journal articles in related fields of cell therapy research prompted concerns about the safety and scientific foundations of the CONCERT-HF study. While none of the articles in question derives from the CONCERT-HF trial itself, out of an abundance of caution the NHLBI sought guidance from CONCERT-HF’s Data and Safety Monitoring Board (DSMB). The DSMB is an independent group of experts that periodically reviews and evaluates study data and makes recommendations to the NHLBI regarding participant safety, data integrity, and study progress. Based on their recommendation, the NHLBI paused the study on October 29, 2018, so that the safety and scientific validity of CONCERT-HF could be re-evaluated.
The DSMB met on November 30, 2018, to review the scientific literature, detailed information, and reports submitted by the CONCERT-HF investigators. They concluded that the scientific basis and rationale for the CONCERT-HF study were sound, that the cell-based products administered to participants met the criteria for clinical use, and that there were no concerns related to participant safety. Therefore, the DSMB recommended that the study continue for those participants whose tissue had been collected already.
The DSMB met again on February 6, 2019, to review a more detailed report on the cell-based product manufacturing process prepared by an Independent External Expert Panel (IEEP), and to evaluate an interim analysis of study results. In light of the IEEP report, the DSMB concluded that the CONCERT-HF cell product be deemed acceptable for clinical administration to participants.
Based on the interim analysis, the DSMB determined that the data collected from the participants currently enrolled in the study who have already undergone tissue collection will likely provide sufficient information to answer the key study questions with rigor. The NHLBI accepted these recommendations.
At a regularly scheduled meeting on March 8, 2019, the DSMB had no actionable safety concerns and recommended that the study continue. Additionally, the DSMB recommended submission of another interim analysis that included 12-month efficacy and safety data. The NHLBI accepted these recommendations.
At a regularly scheduled meeting on September 13, 2019, the DSMB reviewed the requested interim analysis report and recommended that the study continue. Additionally, the DSMB recommended removal of the pause on recruitment. The NHLBI accepted these recommendations and determined that the study should continue without additional recruitment.
Treatment of study participants that were affected by the October 2018 pause in the study was completed by April 2019, and collection of 12-month outcomes for all participants was completed in June 2020.