Efficacy of Valsartan in Reducing Aortic Root Dilatation in Pediatric and Young Adult Patients with Marfan-Type Heritable Thoracic Aortic Diseases

The primary objective of this study is to evaluate the efficacy of **valsartan** in slowing down aortic root dilatation in children and young adults with Marfan-type heritable thoracic aortic diseases. This is clinically relevant as it aims to address the progression of aortic root enlargement, which is a significant risk factor for aortic dissection and other cardiovascular complications in patients with Marfan syndrome and related conditions.

Secondary objectives include:

• Evaluating the annual difference in the aortic root diameter expressed in z-scores, indexed to sex and body surface area (BSA), measured by transthoracic echocardiography and expressed as z-score/year.
• Assessing the absolute annual difference in aortic root diameter in millimeters as measured by angio-CT.
• Determining the absolute annual difference in the diameter of the aortic annulus, sinotubular junction, distal ascending aorta, aortic arch, thoracic aorta, and abdominal aorta, assessed by transesophageal echocardiography and expressed in mm/year.
• Evaluating the annual difference in the diameter of the aortic annulus, sinotubular junction, distal ascending aorta, aortic arch, thoracic aorta, and abdominal aorta expressed in z-score (sex-indexed and BSA), assessed by transesophageal echocardiography and expressed as z-score/year.
• Investigating the difference in aortic root diameter in subgroups of patients with different types of heritable thoracic aortic diseases (HTAD), identified by genetic testing.
• Monitoring acute aortic syndromes such as aortic dissection, aortic perforation, intramural hematoma, and penetrating ulcer, as well as aortic dilatation requiring surgery and death from cardiovascular causes.
• Recording adverse events related to or potentially related to the administered pharmacotherapy, including serious adverse events (SAE) and adverse events (AE).
• Comparing systolic and diastolic blood pressure values based on Holter blood pressure measurements.

The clinical trial involves a study population comprising both **male** and **female** participants, aged between 1 and 39 years, diagnosed with Marfan Syndrome or related heritable thoracic aortic diseases. The trial aims to evaluate the efficacy of valsartan in slowing down aortic root dilatation in this demographic. Participants were selected based on the presence of aortic root dilatation with a z-score of 2 or greater, and a confirmed diagnosis of a syndrome classified under the HTAD group, which includes conditions such as Loeys-Dietz syndrome and the vascular type of Ehlers-Danlos syndrome. The trial includes a vulnerable population, and informed consent was obtained from all participants. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed to evaluate the efficacy of **valsartan** in slowing down aortic root dilatation in children and young adults with Marfan-type heritable thoracic aortic diseases. This study is a randomized, double-blind, placebo-controlled multicenter trial. The trial is expected to run from February 2023 to May 2027, with participant involvement lasting up to 36 months. The trial will include several key phases, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age (1-39 years), diagnosis of a syndrome classified under the HTAD group, and aortic root dilatation (z-score ≥ 2). Participants will be randomly assigned to receive either Valsacor® 40 mg film-coated tablets, VALZEK 80 mg tablets, or a placebo, administered orally. The primary endpoint is the absolute annual difference in aortic root diameter measured by transthoracic echocardiography, expressed in mm/year. Secondary endpoints include the annual difference in aortic root diameter expressed in z-scores and the absolute annual difference assessed by angio-CT. Follow-up visits will be scheduled periodically to monitor the participants' health and the progression of aortic root dilatation. The end-of-study visit will conclude the trial, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with the study protocol, or withdraw consent. The trial aims to provide valuable insights into the therapeutic potential of valsartan for managing aortic root dilatation in this patient population.

The clinical trial involves the administration of **Valsartan** in two different formulations as the experimental medication. The first formulation is **Valsacor® 40 mg film-coated tablets**, manufactured by TAD PHARMA GMBH. This pharmaceutical form is a film-coated tablet, and the active substance is **valsartan**, a chemical compound. The tablets are administered orally. The maximum daily dose is 320 mg, with a total maximum dose of 345,600 mg over a treatment period of 36 months. The tablets are repackaged in unit packages containing 30 tablets per bottle, with external labeling consistent with the submission documentation dated July 25, 2022. The investigational medicinal product is released for use in a non-commercial clinical trial by a Qualified Person.

The second formulation is **VALZEK, 80 mg tablets**, produced by CELON PHARMA S.A. This formulation is also a tablet with **valsartan** as the active substance, administered orally. Similar to the first formulation, the maximum daily dose is 320 mg, and the total maximum dose is 345,600 mg over a 36-month treatment period. The tablets are repackaged in unit packages of 30 tablets per bottle, with labeling consistent with the submission documentation dated July 25, 2022. The investigational medicinal product is released for use in a non-commercial clinical trial by a Qualified Person.

In addition to the experimental medications, the study includes two placebo treatments, designated as **PL1** and **PL2**. These placebos do not contain any active substance and are used to maintain the double-blind nature of the trial. The placebo treatments are administered in a manner consistent with the experimental medications to ensure blinding is maintained throughout the study.

The efficacy of **valsartan** in slowing down aortic root dilatation in children and young adults with Marfan-type heritable thoracic aortic diseases will be assessed through a randomized, double-blind, placebo-controlled multicentre trial. The primary endpoint for evaluating efficacy is the absolute annual difference in aortic root diameter, measured by transthoracic echocardiography and expressed in millimeters per year. Secondary endpoints include the annual difference in aortic root diameter expressed in z-scores, indexed to sex and body surface area (BSA), also measured by transthoracic echocardiography and expressed as z-score per year, as well as the absolute annual difference in aortic root diameter expressed in millimeters as assessed by angio-CT.