Phase I Randomized Study of Cardiac Stem Cells in Patients With Hypoplastic Left Heart Syndrome: The CHILD Trial

Hypoplastic left heart syndrome (HLHS) requires a series of 3-staged palliative operations, in which the right ventricle (RV) assumes systemic circulation under increased pressure-overload conditions. These patients have a shortened lifespan, often due to RV dysfunction. Neonatal cardiac progenitor cells (nCPCs) improve RV performance in animal models of pressure overload-induced RV dysfunction, as is experienced by HLHS patients.

The authors conducted a phase 1 trial to assess the impact of autologous nCPCs injected into the RV myocardium during stage 2 operation. The primary endpoints were safety and feasibility, with efficacy assessed by evaluating RV size and function over a 1-year period.

The study enrolled HLHS patients in 2 groups. Group A consisted of 9 consecutive patients who received nCPC injections during their stage 2 operation. Group B involved a multicenter, randomized, double-blind trial comparing nCPC injections (n = 8) to standard-of-care (SOC) treatment (n = 8). The treatment arm received nCPC injections into the RV myocardium. All caregivers and cores except the surgeon were blinded to treatment.

The trial met its primary safety and feasibility endpoints. However, the primary efficacy endpoint-changes in RV size or function measured by cardiac magnetic resonance and echocardiography-was not achieved. Despite this, secondary outcomes indicated potential clinical benefits. In group B, the mean major adverse cardiac events rates per 100 person-days were higher in the SOC arm (0.23) compared to the nCPC arm (0.00; P = 0.013) after stage 2 operation. The total 1-year in-hospital length of stay due to cardiac and vascular diseases was 15 days and 2 days per 100 person-days for the SOC and nCPC arms, respectively (P = 0.035). Mechanistic studies revealed that, on average, patients in the nCPC arm exhibited noticeable increases from baseline in plasma levels of VEGFC, VEGFD, TNF-α, and monocyte chemotactic protein-1 compared to the SOC arm by postoperative day 5, though the differences were not statistically significant after false discovery rate adjustment. Whereas subject numbers were insufficient to show significance for the composite endpoint of death or listed for transplantation for group B, when combining both groups A and B, no events were seen in the combined nCPC arms and 3 events were in the SOC arm (log-rank P = 0.005).

Injecting nCPCs into the RV during the stage 2 operation for HLHS patients appears to be safe but does not improve RV function. These findings warrant the initiation of a phase 2 trial. (The CHILD Trial: Hypoplastic Left Heart Syndrome Study [CHILD]; NCT03406884).