Clinical Trials in Hypertrophic Cardiomyopathy Therapy: A Comprehensive Analysis of Trials Registered in Global Clinical Databases

Figures & data

Figure 1 Flowchart of trial selection. (A) Venn diagram of the ClinicalTrials.gov database and ICTRP database co-targets. (B) Flowchart of inclusion criteria for clinical trial selection. ICTRP, International Clinical Trials Registry Platform.

Table 1 Characteristics of All Included Trials (n = 137)

Variable	Subgroup	N (%)
Source Register
	ANZCTR	4 (2.92)
	ChiCTR	5 (3.65)
	ClinicalTrials.gov	117 (85.40)
	EU Clinical Trials Register	8 (5.84)
	ISRCTN	1 (0.73)
	JPRN	1 (0.73)
	Netherlands Trial Register	1 (0.73)
Year
	Prior to 2005	8 (5.84)
	2006–2011	19 (13.87)
	2012–2017	38 (27.74)
	2018–2022	72 (52.55)
Status
	Active, not recruiting	15 (10.95)
	Authorised	8 (5.84)
	Completed	43 (31.39)
	Recruiting	39 (28.47)
	Suspended	1 (0.73)
	Terminated	5 (3.65)
	Withdrawn	3 (2.19)
	Unknown status	23 (16.79)
Study results
	Has results	15 (10.95)
	No results available	122 (89.05)
Age group
	Adult	11 (8.03)
	Adult+Older Adult	109 (49.56)
	Child	1 (0.73)
	Child+Adult	6 (4.38)
	Child+Adult+Older Adult	9 (6.57)
	Not Applicable	1 (0.73)
Funded by
	Industry	32 (23.36)
	NIH	7 (5.11)
	Other	77 (56.20)
	Other+Industry	13 (9.49)
	Other+NIH	4 (2.92)
	Not Applicable	4 (2.92)
Locations
	Africa	1 (0.73)
	Asia	21 (15.33)
	Europe	59 (43.07)
	Global	12 (8.76)
	North America	37 (27.01)
	Oceania	6 (4.38)
	South America	1 (0.73)

Abbreviations: ANZCTR, Australian New Zealand Clinical Trials Registry; ChiCTR, Chinese Clinical Trial Registry; ICTRP, International Clinical Trials Registry Platform; JPRN, Japan Primary Registries Network; NIH, National Institutes of Health.

Figure 2 Correlation between the number of trials and beginning year in all 137 included trials.

Table 2 Study Design Elements of Included Trials (n = 137)

Variable	Subgroup	N (%)
Primary purpose
	Basic Science	6 (4.38)
	Device Feasibility	2 (1.46)
	Diagnostic	10 (7.30)
	Screening	3 (2.19)
	Supportive Care	3 (2.19)
	Treatment	106 (77.37)
	Not applicable	7 (5.11)
Allocation
	Randomized	81 (59.12)
	Non-Randomized	15 (10.95)
	Not applicable	41 (29.33)
Intervention model
	Parallel Assignment	69 (50.36)
	Single Group Assignment	37 (27.01)
	Crossover Assignment	16 (11.68)
	Sequential Assignment	3 (2.19)
	Not applicable	12 (8.76)
Masking
	Single blind	12 (8.76)
	Double blind	22 (16.06)
	Triple blind	11 (8.03)
	Quadruple blind	17 (12.41)
	None (Open Label)	63 (45.99)
	Not applicable	12 (8.76)
Phases
	Phase 1	12 (8.76)
	Phase 2	38 (27.74)
	Phase 2+Phase 3	4 (2.92)
	Phase 3	12 (8.76)
	Phase 4	11 (8.03)
	Not Applicable	60 (43.80)
Enrollment
	<50	66 (48.18)
	50–100	34 (24.82)
	101–200	23 (16.79)
	201–500	12 (8.76)
	>500	1 (0.73)
	Not applicable	1 (0.73)

Figure 3 (A) Overview of investigated drugs and (B) their classification through Medical Subject Headings (MeSH).

Notes: Data from MeSH Tree, https://meshb.nlm.nih.gov/; Mavacamten formerly known as MYK-461; Aficamten formerly known as CK-3773274; Binimetinib formerly known as MEK162; Ninerafaxstat formerly known as IMB-1018972; Vastarel formerly known as Trimetazidine dihydrochloride; TY-0305 formerly known as Cibenzoline.

Figure 4 Overview of NCI Thesaurus Tree for investigated drugs. (A) Proportion of each classification via NCI Thesaurus Tree; (B) Proportion of agents affecting the cardiovascular system; (C) Proportion of drugs used as myosin inhibitors.

Note: Data from NCI Thesaurus Tree, https://ncit.nci.nih.gov.

Figure 5 Overview of Investigated Targets. (A) Diagram of the formulated drug-target network. (B) Graph showing the top seven agents tested in the clinical trials assessed.

Table 3 Characteristics of High-Quality Clinical Trials in HCM Therapy

Drug	Trial ID	Recruit Status	Phases	Primary Outcome Measures	US FDA Approval Status	Targets	NCI Thesaurus Tree	Clinical Pharmacology
Mavacamten	NCT02356289	Completed	Phase 1	Incidence of AEs	Approved	Myosin-7	Myosin Inhibitors	Modulates the number of myosin heads, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation; Diminishes dynamic LVOT obstruction, leading to improved cardiac filling pressures.^Citation36
	NCT03442764	Completed	Phase 2	Incidence of AEs
	NCT03470545	Completed	Phase 3	Clinical response of pVO2 and NYHA functional class
	NCT03723655	Active, not recruiting	Phase 2/3	Incidence of AEs
	NCT04349072	Active, not recruiting	Phase 3	Evaluate adults with oHCM who are eligible for SRT.
	NCT05174416	Recruiting	Phase 3	Valsalva LVOT peak gradient
	NCT05582395	Not yet recruiting	Phase 3	KCCQ-23 CSS and pVO2
Trientine	NCT04706429	Authorized	Phase 2	Left ventricular mass indexed to body surface area	Unapproved for HCM; Approved for adult patients with stable Wilson’s disease	Glypican-1	Chelating Agent	Discerning Copper(II) Chelator; Ameliorates LVH by reducing hypertrophy and fibrosis, improving mitochondrial function and energy metabolism.^Citation40
Aficamten	NCT04219826	Active, not recruiting	Phase 2	Incidence of AEs	Unapproved for HCM	*Myosin^Citation41	Myosin Inhibitors	Exhibits specific and reversible binding to myosin; Diminishes actin-myosin cross-bridge interactions and decreasing Contractility; Brings About Reductions In LVOT Gradients.^Citation42
	NCT05186818	Recruiting	Phase 3	pVO2
Empagliflozin	NCT05182658	Not yet recruiting	Phase 3	pVO2	Unapproved for HCM; Approved for type 2 diabetes	Sodium/Glucose Cotransporter 2	Enzyme Inhibitor	Improves Mitochondrial Function; Reduces LVEF; Decreases The Risk Of Worsening HF.^Citation43–45
Esmolol	NCT05073094	Recruiting	Phase 4	The peak concentration of Troponin I	Unapproved for HCM; Approved for short-term use in controlling supraventricular tachycardia	Beta-1 Adrenergic Receptor	Adrenergic Agonist
Midodrine	EUCTR2015-003521-34-FR	Authorized	Phase 2	Walk distance	Unapproved for HCM; Approved for low blood pressure (hypotension)	Alpha-1A Adrenergic Receptor	Adrenergic Agonist	Optimizes therapy for HF; Up-titration of neurohormonal antagonist therapy.^Citation46,Citation47
						Alpha-1B Adrenergic Receptor
						Alpha-1D Adrenergic Receptor
Ninerafaxstat	NCT04826185	Recruiting	Phase 2	Incidence of AEs	Unapproved for HCM	*3-Ketoacyl Coa Thiolase^Citation48	Enzyme Inhibitor	Improves myocardial energetic.^Citation49
Perhexiline	NCT04426578	Recruiting	Phase 2	Change in LVH	Unapproved for HCM	Carnitine O-Palmitoyltransferase 1, Liver Isoform	Calcium Channel Blockers	Enhanced ; Improvement in easing diastolic dysfunction during exercise.^Citation50
						Potassium Voltage-Gated Channel Subfamily H Member 2
Trimetazidine	EUCTR2018-000029-29-NL	Authorised	Phase 2	Myocardial efficiency	Unapproved for HCM; France FDA approved for angina pectoris	3-Ketoacyl-Coa Thiolase, Mitochondrial	Cardiotonic agent	Attenuate the ischemic HF^Citation51
Valsartan	NCT01912534	Completed	Phase 2	Composite z-score	Unapproved for HCM; Approved for hypertension in adults	Type-1 Angiotensin II Receptor	Antihypertensive agent	Improves the composite Z-Score^Citation52
LCZ696	NCT04164732	Recruiting	Phase 2	pVO2	Unapproved for HCM	Neprilysin	Angiotensin receptor antagonists	Blood pressure lowering^Citation53

Note: *The data is not available in the DrugBank database and the NCI Thesaurus Tree but obtained from literature.

Abbreviations: LVEF, left ventricular ejection fraction; HF, heart failure; LVH, left ventricular hypertrophy; LVOT, left ventricular outflow tract; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; oHCM, obstructive hypertrophic cardiomyopathy; SRT, septal reduction therapy; KCCQ-23 CSS, kansas city cardiomyopathy questionnaire (23-item) clinical summary score; pVO2, peak oxygen consumption; AEs, adverse events.

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