Current State of Hypertrophic Cardiomyopathy Clinical Trials

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder with a very large global burden for which more therapeutic management regimens are required. Objectives: In this study, the authors explore HCM-related clinical trials, determine the shortcomings leading to the lack of development of new HCM therapies, and attempt to shed light on potential areas for improvement. Methods: In January 2019, the authors completed a search on ClinicalTrials.gov for all therapeutic and interventional clinical trials involving HCM, without any limits for location or date. Information on trial characteristics such as phase, start and end dates, sample size, experimental intervention, publications, study design, selection criteria, and results were collected and analyzed. Results: Sixty-three trials met the selection criteria. The average trial duration across phases was around 3 years. Around one-half of the trials were conducted in North America (United States and Canada) and 44% of the trials were in their early phases (I and II). Approximately one-third of the trials were completed. Only 14 publications were produced from all the clinical trials studied. Conclusions: The study revealed a low number of trials, lack of geographic diversity, and scarcity of published results concerning HCM clinical trials. Proper management of HCM trials is of vast importance to achieve effective therapies. The authors report no relationships that could be construed as a conflict of interest. From the *Faculty of Medicine, American University of Beirut, Beirut, Lebanon; yNeuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon; zLebanese Institute for Biomedical Research and Application, School of Arts and Sciences, Lebanese International University, Beirut, Lebanon. Correspondence: H. H. Khachfe (hhk15@mail.aub. edu). GLOBAL HEART © 2019 World Heart Federation (Geneva). Published by Elsevier Ltd. All rights reserved. VOL. 14, NO. 3, 2019 ISSN 2211-8160/$36.00. https://doi.org/10.1016/ j.gheart.2019.07.005 Cardiovascular disease is the number 1 cause of death worldwide [1,2]. Hypertrophic cardiomyopathy (HCM) is a common subtype of cardiovascular disease, which has a prevalence of 1 in 500 of the general population [3]. HCM is has a genetic component, making it an inherited disease. In fact, it is the most common genetic cardiovascular disorder [4]. It is can be caused by any 1 of 1,400 mutations in 11 or more genes that encode proteins related to cardiac sarcomeres [3]. HCM is one of the most common causes of sudden cardiac death in the young population and athletes, with most patients suffering from the disease being unaware because of the lack of any substantial symptoms [5,6]. For clinical diagnosis of the disease, echocardiography or cardiovascular cardiac magnetic resonance are required to show the hypertrophied tissue, which is the left ventricle in most cases [7,8]. The development of HCM can occur via several different pathways/mechanisms. HCM has an autosomal dominant transmission, making it difficult to skip a generation [9]. It may also develop in individuals without any significant family history via de novo mutations [9]. HCM is caused by mutations in genes that encode for 1 sarcomere protein, examples of which are troponin, titin, actin, and beta-myosin heavy chain [10e12]. These said mutations cause abnormalities in the structure of cardiac GLOBAL HEART, VOL. 14, NO. 3, 2019 September 2019: 317-325 myocytes and myofibrils that will eventually cause problems in conduction and contraction throughout the heart [12]. These abnormalities lead to the disease known as HCM. Despite having gained a significant understanding of HCM, and with great developments in the management of the disease with interventional procedures, device installment, and surgery, pharmacological therapy has yet to evolve from its primal objectives of simple symptom relief and functional capacity improvement [13]. In fact, in a recent survey of all literature pertaining to any pharmacological regimen ever used to treat HCM, only 45 studies were identified over the last 60 years (i.e., <1 per year), enrolling a total of 2,121 patients with HCM [14]. To this date, no pharmacological (medical) treatment has proved to reduce the risk of sudden cardiac death or prolong patient survival [13]. Survival outcomes, clinical benefits, and clinical benefit rely on the discovery of new therapeutic regimens. Therefore, it is of vast importance to analyze and evaluate new therapies via clinical trials as well as present patients with HCM with the opportunity to participate in said trials. By doing so, we will be able to generate valuable data concerning HCM management and decrease investment in ineffective management techniques.


Conclusions:
The study revealed a low number of trials, lack of geographic diversity, and scarcity of published results concerning HCM clinical trials. Proper management of HCM trials is of vast importance to achieve effective therapies. Cardiovascular disease is the number 1 cause of death worldwide [1,2]. Hypertrophic cardiomyopathy (HCM) is a common subtype of cardiovascular disease, which has a prevalence of 1 in 500 of the general population [3]. HCM is has a genetic component, making it an inherited disease. In fact, it is the most common genetic cardiovascular disorder [4]. It is can be caused by any 1 of 1,400 mutations in 11 or more genes that encode proteins related to cardiac sarcomeres [3]. HCM is one of the most common causes of sudden cardiac death in the young population and athletes, with most patients suffering from the disease being unaware because of the lack of any substantial symptoms [5,6]. For clinical diagnosis of the disease, echocardiography or cardiovascular cardiac magnetic resonance are required to show the hypertrophied tissue, which is the left ventricle in most cases [7,8].
The development of HCM can occur via several different pathways/mechanisms. HCM has an autosomal dominant transmission, making it difficult to skip a generation [9]. It may also develop in individuals without any significant family history via de novo mutations [9]. HCM is caused by mutations in genes that encode for 1 sarcomere protein, examples of which are troponin, titin, actin, and beta-myosin heavy chain [10e12]. These said mutations cause abnormalities in the structure of cardiac myocytes and myofibrils that will eventually cause problems in conduction and contraction throughout the heart [12]. These abnormalities lead to the disease known as HCM.
Despite having gained a significant understanding of HCM, and with great developments in the management of the disease with interventional procedures, device installment, and surgery, pharmacological therapy has yet to evolve from its primal objectives of simple symptom relief and functional capacity improvement [13]. In fact, in a recent survey of all literature pertaining to any pharmacological regimen ever used to treat HCM, only 45 studies were identified over the last 60 years (i.e., <1 per year), enrolling a total of 2,121 patients with HCM [14]. To this date, no pharmacological (medical) treatment has proved to reduce the risk of sudden cardiac death or prolong patient survival [13]. Survival outcomes, clinical benefits, and clinical benefit rely on the discovery of new therapeutic regimens. Therefore, it is of vast importance to analyze and evaluate new therapies via clinical trials as well as present patients with HCM with the opportunity to participate in said trials. By doing so, we will be able to generate valuable data concerning HCM management and decrease investment in ineffective management techniques.
In this work, we present an overview of clinical trials on HCM, explore their characteristics, and extrapolate conclusions on whether goals of therapies are being met.

MATERIALS AND METHODS Search strategy and selection criteria
Data on clinical trials were retrieved from Clinical-Trials.gov, which is a registry that adds a large number of entries each week. Submission to this registry requires providing detailed information about the respective trial, such as history and a brief description of the registered protocol. Analysis and conclusion production on clinical trial data from this registry has been previously explained [15e18].
In January 2019, a search was conducted on Clin-icalTrials.gov for all clinical trials related to HCM without putting any restriction for date or location. A total of 7 trials of 70 were removed, as they were noninterventional and nontherapeutic studies. This was done following the Vanderbeek et al [19] elimination schema ( Figure 1).

Data collection
All details pertaining to the trials were acquired, including status (completed, active, recruiting, not recruiting, suspended, terminated, etc.), start and end dates, phase (I, II,  II/III, IV), primary endpoints, sample size, selection criteria, study design, location, results, experimental interventions, and publications.

Retrieving publications
Publications stemming from the trials were obtained using the registry number (NCTID) found on ClinicalTrials.gov. NCTID identifiers were used on various search engines such as PubMed/Medline and Embase/Scopus to retrieve the corresponding publications present, if any. If the trial produced any publication, then the NCTID identifier was found as part of the research paper. Publications were collected and reviewed by 2 investigators (H.H.K., H.S.) to identify the ones that reported primary results from the corresponding trial.

Overview
Only 63 trials met the criteria we set for our study. Table 1 shows the trials assorted by different characteristics, such as phase, status, number of patients, location, duration, etc. A total of 4,260 patients were enrolled in all clinical trials in our survey. Trials were dispersed over 15 different countries, in which around one-half of them were found in North America alone (United States and Canada) ( Table 1 and Figure 2). Trial duration was found in almost all trials in our study, and the average duration of each trial was around 3 years long. Most trials were in the early stages, with 44% were in phase I and II ( Figure 3). Only 24 (38%) of all trials were completed, while 6 trials ended before completion, either being terminated or withdrawn.

Publications linked to trials
From all trials in this study, only 14 publications had identifications codes linking them to clinical trials related to HCM (Table 2) [20e32]. Around one-half of these publications, 7 (50%), were from clinical trials in phase II. Of the 24 completed clinical trials, only 8 (33%) produced publications.

Phase I trials
Of all trials, only 7 (11%) were in phase I (Table 1). More than one-half of these trials were completed (57%). A total of 349 patients were found in phase I trials, in which the average number of patients per trial was 49.9. Four of these trials were found in North America, while the other 3 were conducted in Europe ( Table 1). The average duration of trials in phase I was 3.8 years. One publication (NCT01537 926) was associated to a trial in phase I ( Table 2).

Phase II trials
The majority of HCM-related clinical trials was found to be in phase II (33%) ( Table 1). More than one-half of the clinical trials in phase II were completed (52%). The greatest number of patients was found to be in phase II, with 1,356 patients, in which the average number of patients per trial was 67.8 ( Table 2). The average duration of phase II trials was 2.9 years. Thirteen of the trials were conducted in North America, while the remaining 8 were conducted in Europe. Seven publications were linked to clinical trials in phase II (NCT00500552, NCT01447654, NCT01447654, NCT016 96370, NCT01150461, NCT00430833, and NCT01 912534) ( Table 2).

Phase II/III trials
Only 4 (6%) trials were in phase II/III (Table 1) (Table 1). Only 1 trial was completed. The average duration of trials in phase II/III was 3.5 years. Three of the trials were conducted in North America, while the final 1 was conducted in Europe. Three publications were produced from trials in phase II/III (NCT02291237, NCT00319982) ( Table 2).

Phase III trials
Six trials were in phase III (10%) ( Table 1). There were 384 patients enrolled in phase III trials, and there were 64 patients per trial, on average ( Table 1). The average duration of trials in phase III was 2.8 years. Three trials were conducted in North America, 2 in Europe, and 1 in an unknown location. Only 1 publication was produced from a trial in phase 3 (NCT00317967) ( Table 2).

Phase IV trials
Seven trials were in phase IV (11%), with 648 patients enrolled and an average patient distribution of 92.5 per trial ( Table 1). The average duration of trials in phase IV was 2.4 years. Four trials were conducted in North America, 2 in Europe, and 1 in China (Table 1 and Figure 2). No publications were published from clinical trials in phase IV.

Unknown phase trials
A total of 18 (29%) trials had no known phase associated to them on ClinicalTrials.gov (Table 1). There were 1,027 patients in this category, with an average of 57.1 patients per trial (Table 1). The average duration of trials was 3 years. Four trials were conducted in North America, 10 were conducted in Europe, 1 was conducted in Brazil, 1 was conducted in China, and 2 had no known location ( Figure 2). Two publications were produced from this category (NCT01631006 and NCT02054221) ( Table 2).

DISCUSSION
Our results highlight the current state of HCM-related clinical trials. Increasing survival rates and improving clinical benefits associated with HCM depends on the discovery of new therapeutic management techniques and regimens. Therefore, it is of great importance to increase new therapies via clinical trials as well as increase the amount of publications correlated to said trials to improve HCM research.

Low number of trials
Since the discovery of HCM in 1957, only 63 therapeutic and interventional clinical trials had been conducted as of January 2019 [33]. The low number of clinical trials may be attributed to a number of different reasons. First, the relatively low prevalence of HCM (1:500) may discourage people from investing and pursuing therapies for a disease with such a low prevalence in the general population [3]. This low prevalence makes HCM a bad investment choice for the pharmaceutical industry [14]. Second, because of the heterogenous nature of the disease, it would be difficult to tailor 1 trial to include all patients with HCM [34]. However, because of the long life need of medication to treat the condition, companies could find some economic benefit in finding appropriate treatments for the disease.
Last, there still remain a number of aspects in the pathophysiology of HCM that are yet to be unexplored. This should prompt increased research to target these unexplored aspects to fully tackle the disease.

Lack of geographic diversity
The results of our study show that HCM clinical trial activity in most nations affected by the disease is scarce.
Although the global burden of the disease has shown to be in 122 of 191 total countries in the world, our dataset shows that clinical trials are being conducted in only 15 countries [35]. A total of 90% of all HCM clinical trials have been conducted in North America and Europe. This can partly be explained by the fact that these 2 groups of countries are considered to be developed nations with adequate infrastructure and resources for research [36].
Other countries around the world lack said infrastructure and resources. For example, our dataset does not contain any entries from Africa, where such resources are scarce [37]. In Ethiopia for example, HCM counts for around 30% of all cardiomyopathy cases diagnosed by echocardiography, according to some studies [38,39]. Because of the global nature of this disease, more efforts must be put from the various nations around the world to try and invest in the treatment of HCM.

Trial duration and lack of published research
The average duration of the clinical trials found in our study was 3 years. The reason behind this duration lies in the general design of a clinical trial, in which obtaining the necessary support and approvals to conduct the respective study needs such time. With adequate time management, the duration needed for starting and completing of any clinical trial may be reduced by eliminating any inefficiencies. The introduction of new master protocols that screen patients according to their various genetic causes   jg SCIENCE  and different pathophysiologies may help assign them to correct trials for interventions that might be effective [40,41]. Only 14 publications have been produced from the 63 HCM interventional clinical trials. Moreover, only 8 of the 24 completed trials were published. According to Jones et al [42], a number of trials will never end up being for a number of reasons, which include obtaining negative results or lack of interest by the authors themselves. However, the publishing of negative results is of vast importance because it may help other researchers understand the reasons behind a failure and may prevent the replication of a similar failed design in the future. In any case, the patients who are enrolled in any trial must have the right to know the results of the trials they participated in. Abstaining from providing results (even negative ones) will decrease the amount of available research on HCM and create problems for future researchers pursing this disease, as well as sponsors who might avoid providing funds for future trials.

Therapeutic benefit
Several trials showed positive outcomes. Ho et al [23] showed that diltiazem (calcium-channel blocker) is a safe drug to use in HCM mutation carriers. The team also proved that the drug appears to stabilize left ventricular hypertrophy within 2 years of starting the medication [23]. The pilot study shows that preemptive therapy may be started for HCM. This may attenuate the phenotypic expression of HCM later in life. Recent studies have claimed that calcium channel blockers still had no role in decreasing the risk of sudden cardiac deaths due to HCM, but further studies similar to this one may change this perception [43]. Another trial that showed good outcomes was one conducted by Penicka et al. [28]. The team proved that candesartan (angiotensin receptor blocker) improved left ventricular function, and induced regression of left ventricular hypertrophy [28]. Increased exercise tolerance was also noted and no side effects were reported in patients. Another trial by Shimada et al [26] also studied the effects of candesartan, showing that it may attenuate and even halt the progression of myocardial hypertrophy and fibrosis in patients with HCM. The latest American College of Cardiology Foundation/American Heart Association guidelines state the usefulness of angiotensin receptor blockers in resolving these issues in patients with HCM remain unclear [44]. Confirmation of the results of this pilot trial may set the path for updating the current guidelines on management of HCM patients.
These findings can help generate substantial promise to revolutionize the management of patients with HCM. Exploring the different genetic causes and pathophysiologies present for HCM may allow the formulation of better targeted therapies based on the studies present previously. More trials must be done to either confirm previous pilot studies or investigate new therapeutic modalities. The results presented in this study about the different clinical trials done may help in changing the current clinical practice regarding HCM. Interventions such as the ones presented previously can shape the future of clinical decisions in HCM management. Thus, comes the need for proper and further research in this domain.

Study Limitations
Our study focused solely on clinical trials that explored patients with HCM, exclusively. We took several precautions and steps to avoid any type of bias or improper analysis. The validity of our results rests on the validity of the data from the original source, ClinicalTrials.gov. Some data might not be up to date, missing, or registered incorrectly on ClinicalTrials.gov.

CONCLUSIONS
Our study sheds light on the current state of HCM-related clinical trials. Our research team believes that the continuous flow of new research and treatments for HCM is paramount. Therefore, assessing past and current HCM clinical trials is vital. This study showed that concerning HCM clinical trials we have a low number of trials, lack of geographic diversity, and low publication rate. These all constitute major obstacles in HCM research. Optimized management of various resources (human, economic, etc.) and time through a proper system can decrease inefficient therapies and pave the way for the more effective ones.