Abstract
Background
Historically, there have been limited clinical trials in pediatric patients with cardiomyopathy or heart failure. Although the number of these studies has increased in recent years, many have failed to meet their primary endpoints. However, these “negative” trials have been invaluable to the field of pediatric cardiology.
Aim of review
This review aims to highlight the importance of negative clinical trials in pediatric cardiology. It focuses on how these trials, despite not meeting their primary objectives, have provided critical insights into safety, drug metabolism, biomarkers, and have contributed to refining trial design for future studies.
Key scientific concepts of review
Negative trials have played a key role in advancing pediatric heart failure treatment by revealing essential data on drug metabolism, particularly across different age groups, and by identifying novel biomarkers for monitoring treatment efficacy. These trials have also led to improvements in trial design, ensuring better patient selection and more accurate evaluation of therapeutic interventions. Despite not meeting their primary endpoints, these studies have provided a foundation for future innovations and have helped shape treatment strategies in pediatric cardiology.
Highlights
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More clinical trials have been performed in recent years in pediatric patients with cardiomyopathy or heart failure.
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Most of these studies have been ‘negative’ trials, meaning the study medication was not found to be associated with an improvement in the primary outcome
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However, these ‘negative’ trials have been incredibly important for the field and have provided important data on safety, drug metabolism, biomarkers, and strategies to refine study design for future trials.
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Clinical trials remain critical important for pediatric cardiology
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Background
Michael Polyani—a physician, researcher, and philosopher—spent the latter part of his career focused on the psychology and politics of human knowledge. He famously stated that “[a]lmost every major systematic error which has deluded men for thousands of years relied on practical experience. Horoscopes, incantations, oracles, magic, witchcraft, the cures of witch doctors and of medical practitioners before the advent of modern medicine, were all firmly established through the centuries in the eyes of the public by their supposed practical successes. The scientific method was devised precisely for the purpose of elucidating the nature of things under more carefully controlled conditions and by more rigorous criteria than are present in the situations created by practical problems” [ ].
The Michelson–Morley experiment is a classic example of the transformative knowledge that can arise from such rigor. The Ether Wind theory of light propagation postulated that the speed of light was faster in the direction of the Earth’s orbit and slower against it [ ]. When physicists Michelson and Morley systemically measured the speed of light in different inertial frames, however, they found that the speed of light was the same in every direction. Because their findings differed from what was the accepted truth, they published their results as a “failed” experiment. Additional studies would later reveal that the speed of light was indeed constant, and many speculate that this work may have played a role in Einstein’s ultimate derivation of the fundamental theory of relativity.
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Aim of review
We present a review of the “negative” clinical trials in pediatric cardiology that have helped elucidate information that is critical to the care of this complex and diverse patient group. This includes crucial information about the natural history of a population, the differential metabolism of medications based on age and/or weight, novel biomarkers and future therapeutic targets, along with quantitative information on the magnitude of benefit/harm. Iterative learning from trials, whether or not they met the primary endpoint, has also led to refinements in patient selection and trial design to address challenges unique to the pediatric population.
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Key scientific concepts of review
3.1
Negative studies can teach important lessons about trial design and variable drug metabolism/effect
Selective β1-blockers are a mainstay of cardiac reverse remodeling in adults with heart failure and have been demonstrated to improve symptoms and survival [ , ]. When carvedilol was studied in a multicenter, randomized, double-blind, placebo-controlled trial of 161 children and adolescents with symptomatic systolic heart failure, however, there was no difference in mortality or hospitalizations when comparing high-dose carvedilol (0.4 mg/kg/dose), low-dose carvedilol (0.2 mg/kg/dose), and placebo [ ]. While carvedilol did not meet the primary endpoint of this study, which was an improvement in clinical heart failure outcomes, the publication of this trial was crucial for several reasons. It highlighted the importance of the adequate powering of a randomized controlled trial. Using the expected incidence of dilated cardiomyopathy at the time of the study and even when assuming a much higher mortality than was observed (10 % mortality at 2 years) and a 20 % improvement with carvedilol, 6000 patients would have been required to demonstrate a survival benefit of carvedilol, if it did exist [ ]. This study included only 161 patients, and the observed rate of mortality in both the carvedilol and placebo groups was quite low—there were a total of 11 deaths in the entire cohort [6 (5.7 %) in the carvedilol and 5 (9.1 %) in the placebo group], 8 of which were related to a cardiovascular cause [4 (3.8 %) and 5 (7.3 %), respectively]. As a result, while there was a numerical difference in outcomes between the two groups, it did not reach statistical significance.
The study also highlighted the importance of studying a new intervention in a uniform population. This trial included a broad age range (infancy to late adolescence), which ultimately led to a study population with the potential for differential drug metabolism. Indeed, a subsequently published pharmacokinetic study of carvedilol in pediatric patients revealed the area under the plasma concentration-time curve (AUC) increased substantially with age at the same weight-based dosing [ ]. To achieve an AUC comparable to that of an adult receiving a total daily dose of 0.7 mg/kg/day, infants (28 days- 23 months), children (2–11 years), and adolescents (12–15 years) required daily doses of 3, 2, and 1 mg/kg/day respectively, divided twice or three times daily, due to faster drug clearance in younger patients. The trial also included both patients with dilated cardiomyopathy and congenital heart disease (CHD); the latter is a particularly complex and heterogenous group of patients that may have a different mechanism of heart failure when compared to patients with cardiomyopathy [ ]. This difference is likely most pronounced in children with single ventricular physiology and a systemic right ventricle, which is particularly important for a trial of β1-blockers, as these patients are often reliant on heart rate for adequate cardiac output, and most adult heart failure medications have only been studied systematically in a morphologic left ventricle. Indeed, a secondary analysis of patients in the pediatric carvedilol trial with two ventricles and a morphologic left ventricle showed an improvement in the left ventricular function and a dose response curve.
3.2
Negative studies can reveal novel primary outcomes
3.2.1
Biomarkers
Lessons from the carvedilol trial informed the design of the PANORAMA-HF trial, a study comparing the efficacy of sacubitril-valsartan and enalapril in pediatric heart failure patients [ ]. Although both cardiomyopathy and congenital heart disease patients were included, heterogeneity was limited by excluding patients with single ventricle physiology, a systemic morphologic right ventricle, restrictive cardiomyopathy, or hypertrophic cardiomyopathy. Eligible patients were stratified at randomization into three groups by age (1: 6 to <18 years, 2: 1 to <6 years, 3: 1 month to <1 year) and functional classification (NYHA/Ross class group I/II and III/IV). Part 1 of the trial incorporated a pharmacokinetic/pharmacodynamic study for all randomized patients, which established the dosing for part 2 of the study—a randomized, double-blind trial over 52 weeks. The target dosing was 3.1 mg/kg BID of sacubitril-valsartan or 0.15 mg/kg BID of enalapril for group 3 and 2.3 mg/kg BID of sacubitril-valsartan or 0.2 mg/kg BID of enalapril for groups 1 and 2. Given an anticipated inability to power the study appropriately if the traditional outcomes of heart failure hospitalizations and mortality were used, the study incorporated a novel global rank primary endpoint of 5 categories (1: death, listed Status 1 A for heart transplant, mechanical circulatory or ventilatory support; 2: worsening heart failure that required an intensification of heart failure therapy with or without hospitalization; 3: worse, 4: unchanged, or 5: improved NYHA/Ross/PGIS categorization).
Somewhat surprisingly, only ~200 of the planned 360 subjects had been enrolled when the Food and Drug Administration (FDA) preemptively approved sacubitril-valsartan for the treatment of heart failure due to systolic dysfunction of a systemic left ventricle in children >1 year old. This approval was based on the results of a pre-specified interim analysis at 12 weeks, that showed a reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) in the sacubitril-valsartan arm (44 % reduction) than was greater than both the enalapril arm (33 % reduction) of this study and what had been observed in the analogous adult trial [ ]. The decrease in NT-proBNP justified approval of the drug based on the Prentice criteria, which state that a specific biomarker can be considered a valid surrogate endpoint if a treatment (i.e., sacubitril-valsartan) has a significant impact on the true clinical endpoint (i.e., death and hospitalization for heart failure) and its biomarker (NT-proBNP), and the biomarker is significantly associated with and explained by the true endpoint [ ].
Ultimately, at study completion, the primary outcome was not met. Sacubitril-valsartan was not superior to enalapril in either the global rank endpoint or its individual components. However, both groups experienced clinically meaningful improvements in heart failure classification, scores on the patient global impression of severity and pediatric quality of life inventory, and the NT-proBNP. This study contributed important information on the safety and efficacy of both drugs in pediatric heart failure and led to pediatric-specific FDA labeling for sacubitril-valsartan, that is crucial for insurance reimbursement, pediatric-specific educational materials, and adequate post-market surveillance in pediatric patients. Of note, the trial was terminated by the sponsor after only 10 group 3 patients had been enrolled, so there are inadequate data on the safety and efficacy of sacubitril-valsartan in infants.
3.2.2
Drug effect
The Prentice criteria were also the basis for pediatric labeling of ivabradine, a selective sinus-node inhibitor. In a randomized, double-blind, placebo-controlled trial of ivabradine in adults with symptomatic, severe heart failure (left ventricular ejection fraction <35 %), an intention-to-treat analysis revealed a ~ 25 % relative reduction in the primary composite outcome of heart failure hospitalizations and mortality in the ivabradine arm [ ]. Subsequent subgroup analyses established both a foundation for lower heart rate as a surrogate for the primary outcome and evidence that the effect of ivabradine was accounted for by heart rate reduction [ ]. Patients in the placebo arm of the trial with the highest heart rates (≥87 bpm) had a 2.34 relative increase in the hazard of the primary outcome compared to those with the lowest heart rates (70 or 71 bpm); indeed, for every beat increase from the baseline heart rate, the risk of primary composite endpoint events increased by 3 %. Given these principles and the similarities between pediatric and adult dilated cardiomyopathy, the FDA granted approval for the use of ivabradine in pediatric patients with dilated cardiomyopathy and symptomatic heart failure after a single, randomized, double-blind, placebo-controlled trial. The study found that 70 % of pediatric patients treated with ivabradine achieved the primary outcome of a ≥ 20 % reduction in heart rate from baseline without inducing bradycardia or symptoms [ ]. Approval was granted despite a lack of association between ivabradine use and classic heart failure outcome measures such as changes in NT-proBNP, heart failure classification, or quality of life. The potential importance of ivabradine being labeled for pediatric use was highlighted by a subsequent, multicenter registry study that demonstrated that an elevated heart rate was independently associated with mortality (adjusted HR 2.6) and mortality or heart transplant (adjusted HR 1.5) in pediatric heart failure patients [ ].
3.3
Negative trials can demonstrate drug safety in pediatrics
Negative trials have also been important for the management of pediatric heart transplant recipients. When compared to standard immunosuppression in adult heart transplant recipients, the use of mammalian target of rapamycin (mTOR) inhibitors, in addition to lower dose calcineurin inhibitors, is associated with improved renal function, comparable rates of rejection, decreased progression of coronary allograft vasculopathy, and a decreased incidence in both skin cancer and post-transplant lymphoproliferative disorder, at the expense of increased infections and dyslipidemia [ ]. Initial retrospective, single center and registry reports of the use of mTOR inhibitors in pediatric heart transplant recipients revealed improved renal clearance in patients receiving an mTor inhibitor compared to standard immunosuppression, but conflicting data on the impact of their use on the incidence of rejection [ ]. The TEAMMATE trial was the first multicenter, randomized clinical trial in pediatric heart transplant that compared the safety and efficacy of everolimus and low-dose tacrolimus to standard immunosuppression (standard-dose tacrolimus and mycophenolate) by creation of a major adverse transplant event (MATE) score [ , ]. The score was a composite metric used to assess the frequency and severity of major transplant-related complications, including coronary allograft vasculopathy, renal dysfunction, acute cellular rejection, antibody-mediated rejection, infection, and PTLD. Preliminary results presented at the American Heart Association Scientific Sessions revealed that there was no difference between the two groups in median MATE score, patients in the everolimus arm did have better estimated renal clearance and drug tolerance and were less likely to have donor specific antibodies and cytomegalovirus infection. While the primary outcome was not met, the TEAMMATE trial did establish the safety of everolimus in a pediatric population and highlight its potential role in patients with chronic kidney disease, sensitization, and/or intolerance of tacrolimus.
3.4
Negative results can highlight an area for concentrated, collaborative study and intervention
Finally, the publication of negative trials can highlight an important area of focus for innovation and collaboration in a rare disease. The current approach to systemic anticoagulation in pediatric patients requiring mechanical circulatory support was driven by an alarming incidence of complications in the early experience. While the initial, prospective, single-group trial of the Berlin EXCOR ventricular assist device revealed improved survival compared to a historical cohort of patients supported with extracorporeal membrane oxygenation (ECMO), adverse events were common in both groups and included major bleeding and infection in ~50 % of patients and stroke in 29 % of patients [ ]. The high stroke rate persisted in a subsequent prospective cohort study of the Berlin EXCOR at 47 centers in the United States [ ]. These data were part of the impetus for the Advanced Cardiac Therapies Improving Outcomes Network (ACTION), which is a multicenter collaboration that leverages expertise across centers and quality improvement initiatives for the rapid dissemination of effective clinical practices. This group piloted a transition from heparin to bivalirudin for anticoagulation in Berlin EXCOR patients in a small group of ACTION centers and observed a significant decrease in the incidence of major neurologic events. These efforts are believed to have contributed to major improvements in outcomes when comparing patients in the post-market surveillance group to those in the initial, multicenter, prospective trial. This included a 44 % decrease in strokes and a 40 % decrease in the frequency of pump exchanges [ ].
3.5
Future directions
There are several pediatric specific studies underway that have leveraged the many lessons learned from the “negative” trials that are referenced above. This includes the SCOUT-HCM trial of mavacamten in adolescent patients with hypertrophic cardiomyopathy (HCM) [ ]. Based on similar mechanisms of HCM in non-syndromic adolescents and adults, the primary endpoint for this study is a decrease in the left ventricular outflow gradient by echocardiogram during a Valsalva maneuver, which can be used as a surrogate for the symptomatic improvement and decrease in NT-proBNP and high sensitivity troponin observed in adult studies [ ]. Unique trial design is especially important for orphan diseases, such as Danon disease, which is a rare, autosomal dominant, X-linked disease caused by a mutation in the LAMP-2B gene that results in impaired autophagy and places male patients at risk for severe cardiomyopathy and mortality in the second and third decades of life. Since the patient population is not large enough to power for changes in survival, a phase 2/3 study of a viral vector that introduces a functional LAMP-2 gene employed a primary outcome of gene expression and change in troponin levels, as these would be the expected effects of successful gene replacement [ ].
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Conclusion
Even when pediatric trials do not meet the pre-specified primary outcome, their completion and publication are critical to the advancement of the field and the optimal care of pediatric cardiology patients. These trials prevent confirmation bias in clinical practice, spur innovation, improve patient safety, and promote resource efficiency. They also uphold our commitment to the principles of the Declaration of Helsinki and to our patients who incur inconvenience and the risk of potential harm by participating in clinical trials. By redefining success in pediatric trials, the pediatric heart failure community can continue to make meaningful strides in improving care and outcomes for this complex and challenging patient population.
CRediT authorship contribution statement
Humera Ahmed: Writing – review & editing, Writing – original draft. Joseph W. Rossano: Writing – review & editing, Conceptualization.
Declaration of competing interest
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JWR – Consultant for Merck, Bristol Myers Squibb, AskBio, Bayer, CRI Biotech, BioMarin. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
This article is part of a special issue entitled: ‘2024 Conference on Cardiomyopathy in Children’ published in Progress in Pediatric Cardiology.
References
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