Study design

A prospective nonrandomized, single-center, single arm pilot trial will be performed in infants and young children who require semilunar heart valve replacement. The study received approval from the Medical University of South Carolina (MUSC) Institutional Review Board Protocol Record 00114653 and the protocol was registered and approved on the ClinicalTrials.gov platform, trial number NCT05372757. The schedule of enrolment, interventions and assessments is shown in Fig 1.

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Fig 1. Schedule of enrolment, interventions, and assessments.

The figure shows Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) schedule of enrolment, interventions and assessments information. **Post-allocation time points occur at 6 months intervals, starting when the first subject undergoes partial heart transplantation and continuing until one year after all subjects have been enrolled.

https://doi.org/10.1371/journal.pone.0280163.g001

Study population

Five patients in need of a heart valve replacement will be included in the study. A study investigator who normally participates in our biweekly pediatric heart center case conference meeting and has access to patient records and surgical referrals for valve replacement will identify potential candidates for the trial. Study investigators will obtain permission from the primary cardiologist or cardiac surgeon prior to approaching parents or legal guardians to discuss participation in the trial. Telemedicine may be utilized to initially discuss the risks and benefits associated with the study with parents or legal guardians of potential subjects who are outpatients, but an in-person meeting will be required for a formal consent discussion. Expectant mothers who are carrying fetuses that are expected to require heart surgery requiring a valve replacement within the first two years of life may be approached for enrollment in the study as well.

The interventional portion of the study will take place in the cardiac operating rooms and in the Pediatric Cardiac Intensive Care Unit at Shawn Jenkins Children’s Hospital at MUSC. Additional observational data will be collected pre- and intraoperatively, and postoperatively on the Cardiac Stepdown Unit and in the outpatient cardiology clinics at MUSC’s Summey Medical Pavilion.

To be eligible to participate in this study, the patients can be either male or female and must meet the following inclusion and exclusion criteria:

Inclusion Criteria

• Children less than 2 years of age who are referred for a cardiac operation that involves a primary semilunar valve replacement, or children less than 2 years of age who are referred for a cardiac operation involves an initial replacement of a previously placed prior homograft, bioprosthetic, or mechanical valve in the aortic or pulmonary position
• Deemed acceptable for partial heart transplantation based on the standard evaluation process used for conventional orthotopic heart transplantation at our center (see S1 Appendix)
• Have insurance approval
• Provide written informed consent of both parents or legal guardians; if there is only one parent or legal guardian, consent from that individual will be adequate.

Exclusion Criteria

• Absolute contraindications for conventional orthotopic heart transplantation:
  • Severe bilateral long segment pulmonary arterial hypoplasia
  • Bilateral pulmonary vein stenosis
  • <34 weeks corrected gestational age
  • Persistent acidosis with a pH <7.1
• Diagnosis of immune deficiency
• Infectious disease
  • Active sepsis
  • Hepatitis B surface antigenemia
  • HIV positivity
• Inability for the parent(s) or legal guardian(s) to understand English or Spanish
• Failure to pass the following psychosocial evaluation:
  • The candidate should reside within four hours ground traveling time from Medical University of South Carolina for a minimum of four to six months post-transplantation to facilitate close follow-up.
  • The candidate’s family should be capable of long-term supportive care of the child and be able to support the medical needs of the candidate in follow-up.
  • Parental (custodial) alcohol and/or substance abuse.
  • Documented parental (custodial) child abuse or neglect.
  • Parent (custodian) with cognitive/psychiatric impairment severe enough to limit comprehension of medical regimen.

Treatment

The evaluations, tests, and procedures below are typically performed as standard clinical care for recipients of a conventional heart transplant or heart valve replacement. No additional study-specific tests or procedures are planned as part of this trial. We will obtain all the information necessary for the research from the electronic medical record as would be consistent with standard practice for a conventional heart transplant or heart valve replacement.

Data management methods

Data will be collected at intervals as described above. Descriptions of confidentiality provisions and data safety monitoring boards (DSMB) are provided in a later section. In order to preserve the confidentiality of the participants, the following interventions will be undertaken:

1. A. Case report forms (CRFs) will be developed prior to the onset of the trial and completed by a study investigator for each patient.
   1. a. An enrollment form will be completed once written informed consent is provided by the parents or legal guardians.
   2. b. Adverse event forms will be completed as needed throughout the operative hospitalization.
2. B. A dedicated Excel database will be developed for the trial.
   1. a. All data from the CRFs will be entered into a dedicated Excel database by a study team member.
3. C. In the case of a subject withdrawing from the trial, the data will be potentially included in the final analysis depending on the time enrolled in the trial.

Missing data will be addressed by omission or analysis as appropriate. Sensitivity analysis will be planned to avoid misleading inference when complete-case analysis is performed.

Quality control methods

The principal investigator or study coordinator will review all CRFs and data within the study database for completeness and accuracy on an annual basis. Recruitment will also be monitored on an annual basis.

Assessment of results

The primary outcomes will be the feasibility and safety of partial heart transplantation. The feasibility will be determined by the ability to perform the new operation in at least one patient per year for three years after enrollment opens. The safety of the procedure will be indicated by survival and re-interventions that are the same or are better than those reported in the literature for patients of similar age undergoing conventional valve replacement. Safety will primarily be defined as patient survival or re-operation or transcatheter reintervention on the transplanted valve at six-month intervals, starting six months after the first subject undergoes a valve transplant, and continuing until one year after all five subjects have been enrolled. Safety will also be assessed by tracking rates of immunosuppression side effects, including development of insulin-dependent diabetes, chronic renal insufficiency, and significant infections.

The secondary outcomes will be valve annulus growth over time, stenosis and regurgitation. The valve annulus diameter will be measured using echocardiography in two planes at baseline and every six months following the operation. The valve annulus Z-score should remain relatively unchanged over time, indicating an increase in valve annulus growth corresponding with an increase in body surface area. This change should correspond to the growth of conventional heart transplants and Ross pulmonary autografts [18–20]. Valve stenosis and regurgitation will be assessed via transthoracic echocardiogram with pulse Doppler and with color Doppler, respectively, every six months following the operation.

Possible risks to participants

This study involves greater than minimal risk with the potential for direct benefit. In conventional heart transplantation, the most serious risks are graft failure, cardiac allograft vasculopathy, infection and acute rejection, which altogether account for the majority of deaths after conventional heart transplantation. The relative importance of these causes of death vary over time post-transplant. Risks of partial heart transplantation are expected to be similar to the risks of standard valve replacement but less than the risks of conventional heart transplant. A complete list of risks is provided in S2 Appendix.

1. The most serious risks are scheduling issues related to donor heart availability and rejection of the transplanted valve. The risk of rejection is theoretically lower compared to a full heart transplant. The risk of death during and after the operation is similar to the risks for standard valve replacement with a homograft. There is no risk of disease developing in the blood vessels that supply the heart (i.e., coronary arteries) and no risk of heart muscle dysfunction given that these tissues are not being transplanted.
2. The surgery will result in a permanent scar in the middle of the chest. This is the same scar that would result from a standard valve replacement or full heart transplant. This scar may require medical follow-up after surgery and may temporarily restrict the subject from exercise and/or sports participation in the future.
3. Open heart surgery involves the risk of death, brain damage, or other organ damage such as kidney injury.
4. The need for blood transfusion during surgery poses a risk of infection from the blood or a reaction to the blood. The risk of infection from transfused blood is extremely low given current screening processes.
5. Patients receiving a partial heart transplant may also become sensitized to the transplanted valve tissue. This will decrease the donor pool if the patient ever requires a heart transplant.
6. There is a risk of loss of confidentiality.
7. There may also be additional risks that are currently unknown.

Possible benefits to participants

The possible benefits to participants may include the need for fewer valve replacement operations and their substantial morbidity and mortality during childhood.

1. The most important advantage of partial heart transplantation is growth of the transplanted valve. This minimizes the morbidity and mortality from successive implant exchanges.
2. Avoiding reoperations will improve neurodevelopmental outcomes as repeat cardiac operations are associated with worse neurodevelopmental outcomes [21].
3. Avoiding reoperations will decrease psychological and financial stress for subjects’ caregivers and families [22].
4. The transplanted valve would be durable without the need for anticoagulation.
5. The transplanted valve may have better valve function with more favorable loading conditions on the ventricular myocardium.
6. Because of fewer surgeries and their risks, the subjects may potentially have longer lifespans.

Data analysis

Data will be exported from the study database for statistical analysis. Given the goal sample size of five participants and lack of control group, simple descriptive statistics will be used.

Confidentiality provisions

All completed CRFs will remain confidential and will be stored in locked cabinets within the locked offices of the study investigators at MUSC, accessible only to study team members. Study data will reside in password-protected computers within locked offices of study investigators at MUSC, accessible only to study team members. All data stored on MUSC servers are password-protected and backed up nightly. The network is protected on multiple levels that include firewalls, intrusion detection software, and continuous monitoring by the Information Services Security Department.

The study investigators will be primarily responsible for monitoring all study patients for the occurrence of adverse events and unanticipated problems as outlined above.

A DSMB will be chaired by a physician and will be used to monitor the progress of this clinical trial and review safety and effectiveness data while the trial is ongoing. DSMB members will be comprised of senior faculty from other institutions, and will include a pediatric transplant cardiologist, a pediatric cardiac intensivist, and a pediatric cardiac surgeon. None of these individuals will be directly involved with the undertaking of this study or affiliated with MUSC.

The DSMB will be responsible for reviewing the research protocol (and any amendments thereof) and the informed consent documents (S3 Appendix) prior to the onset of patient recruitment. The DSMB will meet virtually one month after each of the first three patients are enrolled and annually thereafter to review study data. The study investigators will prepare interim reports, including a summary of outcomes and adverse events, for DSMB review.

The DSMB will consider and review the following: major protocol modifications proposed by the study team; participant recruitment, accrual and retention; confidentiality issues; factors external to the study when relevant, such as scientific or therapeutic developments that may have an impact on the safety of the subjects or the ethics of the trial; and investigator-assigned relationships between the intervention and adverse events. Following each meeting, the DSMB will prepare a written report on the safety and scientific progress of the trial and make recommendations to the study investigators concerning continuation, termination or modification of the trial based on the observed beneficial or adverse effects of the research. The DSMB will also meet at the conclusion of the study, and as needed to review serious adverse events.

A subject will be removed from the study if a parent or legal guardian withdraws consent, or if one of the patient’s primary attending physicians elects to remove the patient from the study. Additionally, all clinicians who are uninvolved with the trial but participate in the care of the subjects will be encouraged to report adverse events to the study investigators. The study investigators will meet every six months to review adverse events and to assess the risk/benefit ratio for continuing the trial.

Any action that results in a temporary or permanent suspension of the trial will be reported as soon as possible by the investigators to the MUSC IRB and DSMB. If the DSMB or IRB requests a temporary or permanent suspension of the trial, they will notify the principal investigator who will promptly notify all co-investigators and the study team. Annually, the principal investigator and study coordinator will meet for data verification and protocol compliance checks. Specifically, these individuals will monitor whether all enrolled subjects met entry criteria, whether any deviations from the study protocol occurred, and whether any patients were prematurely removed from the protocol by managing physicians or withdrawal of parental consent. The principal investigator or study coordinator will review all CRFs and data within the study database for completeness and accuracy on an annual basis.