Evaluation of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI

Study Overview
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Brief Summary
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Mucopolysaccharidoses (MPS) are multisystemic diseases with significant clinical overlap between their types, with cardiac problems being among the most commonly observed manifestations and are also among the main causes of mortality in these patients. For some of the cardiovascular manifestations, such as aortic root dilation and valve diseases, there is no effective treatment currently available. Losartan, on the other hand, has been shown to be an effective drug for dilation of the aortic root, at least in animal models. This study aims to evaluate the safety and efficacy of losartan in patients with MPS VI and other mucopolysaccharidoses.

Detailed Description
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Mucopolysaccharidoses (MPS) are a group of lysosomal diseases characterized by deficiency of enzymes responsible for the degradation of glycosaminoglycans. MPS are multisystemic diseases with significant clinical overlap between their types, with cardiac problems being among the most commonly observed manifestations and are also among the main causes of mortality in these patients. Enzyme replacement therapy and bone marrow transplantation, despite being well established treatments, are not yet capable of reversing or preventing the progression of some of the cardiological manifestations of MPS. On the other hand, these patients may benefit from other conventional drug or surgical treatment, which can be instituted at an appropriate time if there is a better understanding of how these manifestations progress. In particular, the occurrence of aortic root dilation, although described in animal models, has only recently been evaluated in the studies on mucopolysaccharidoses. In addition, verifying the effectiveness of losartan in controlling these manifestations in the animal model opens the perspective of clinical use of this drug. Losartan is a low-cost drug and, if its efficacy is demonstrated, may represent an accessible therapy directed at the unmet needs of these patients.

Official Title
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A Randomized Clinical Trial to Evaluate the Effects of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI

Conditions
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Mucopolysaccharidosis IV A, Mucopolysaccharidosis VI, Mucopolysaccharidoses, MPS IV A, MPS VI, MPS - Mucopolysaccharidosis, Morquio A Syndrome, Morquio Syndrome A, Morquio Syndrome

Intervention / Treatment
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* Drug: Losartan
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed biochemical or molecular diagnosis of MPS VI or MPS IVA. Age between 10 and 40 years. Presence of aortic root diameter greater than 1.0 standard deviation, as determined by local measurement. Be in a stable treatment regime in the last 3 months (without performing Enzyme replacement therapy (ERT), or performing ERT on a regular basis). Patient who agree to participate in the study protocol by signing a free informed consent form. Exclusion Criteria: Patient who underwent previous aortic surgery. Patient with aortic root diameter greater than 5 cm. Patient on angiotensin-converting-enzyme (ACE) inhibitor. In case of use of beta-blocker, or calcium channel blocker, patient without adequate control of blood pressure in the last 3 months. Patients with previous adverse events related to treatment with losartan or contraindication to this treatment. Inability, in the opinion of the investigator, to complete the study procedures.

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Experimental group: 15 patients, both sexes, will receive Losartan 25 mg orally for 12 months. Control group: 15 patients, both sexes, will receive oral placebo for 12 months. Eligible research participants for treatment will be randomly assigned to a treatment group or a control group in a ratio of 1: 1. The groups will be stratified by age and type of MPS in the following strata: A) Diagnosis of MPS IVA: 20 patients expected B) Diagnosis of MPS VI: 10 patients expected
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Losartan<br>Losartan group: 15 patients, both sexes, will receive Losartan 0.4 to 1.4 mg/kg/day orally for 12 months. | Drug: Losartan<br>* Losartan group: 15 patients, both sexes, will receive Losartan 0.4 to 1.4 mg/kg/day orally for 12 months.<br>|
| Placebo Comparator: Placebo<br>Placebo group:15 patients, both sexes, will receive oral placebo for 12 months. | Drug: Placebo<br>* Placebo group: 15 patients, both sexes, will receive oral placebo for 12 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events related to losartan use | The frequency of adverse events after 12 months will be compared among the groups | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Z score of maximal aortic root diameter measured by Valsalva sinus | Reduction over time in the Z score of maximal aortic root diameter measured by Valsalva sinus echocardiogram between the baseline assessment and 12 months after treatment with losartan. | 12 months | 
| Changes of serum levels of transforming growth factor (TGF-Beta-1) | Changes of serum levels of transforming growth factor (TGF-Beta-1) between baseline and 12 months | 12 months | 
| Changes of serum levels of brain-type natriuretic peptide (BNP) | Changes of serum levels of brain-type natriuretic peptide between baseline and 12 months | 12 months | 
| Changes of serum levels of N-terminal pro b-type natriuretic peptide (NT-ProBNP) | Changes of serum levels of N-terminal pro b-type natriuretic (NT-ProBNP) peptide between baseline and 12 months | 12 months | 
| Changes of serum levels of creatine kinase-myocardial ban (ck-mb) | Changes of serum levels of creatine kinase-myocardial ban (ck-mb) between baseline and 12 months | 12 months | 
| Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6) | Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6) between baseline and 12 months | 12 months | 
| Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) | Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) between baseline and 12 months | 12 months | 
| Changes of serum levels of Endocan-1 (ESM-1) | Changes of serum levels of Endocan-1 (ESM-1) between baseline and 12 months | 12 months | 
| Changes of serum levels of Placental growth factor (PLGF) | Changes of serum levels ofPlacental growth factor (PLGF) between baseline and 12 months | 12 months | 
| Changes of serum levels of Fatty acid binding protein 3 (FAPB3) | Changes of serum levels of Fatty acid binding protein 3 (FAPB3) between baseline and 12 months | 12 months | 
| Changes of serum levels of Fatty acid binding protein 4 (FAPB4) | Changes of serum levels of Fatty acid binding protein 4 (FAPB4) between baseline and 12 months | 12 months | 
| Changes of serum levels of Oncostatin M | Changes of serum levels of Oncostatin M between baseline and 12 months | 12 months | 
| Changes of serum levels of Troponin I | Changes of serum levels of Troponin I between baseline and 12 months | 12 months | 
| Changes of ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months. | Reduction over time in the ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months. | 12 months | 
| Changes in mitral valve regurgitation | Alteration of the parameter of mitral valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months. | 12 months | 
| Changes in aortic valve regurgitation | Alteration of the parameter of aortic valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months. | 12 months | 
| Changes in ejection fraction | Alteration of the ejection fraction measurement as assessed by echocardiography between the baseline and 12 months. | 12 months | 
| Changes in left ventricular longitudinal strain | Alteration of the measurement of left ventricular longitudinal strain as assessed by echocardiography between the baseline and 12 months. | 12 months | 
| Changes in E/A ratio | Alteration of the parameter E/A ratio as assessed by echocardiography between the baseline and 12 months . | 12 months | 
| Changes in E/e' ratio | Alteration of the parameter E/e' ratio as assessed by echocardiography between the baseline and 12 months. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidoses, Losartan, Aortic root dilatation, Echocardiogram, MPS IV, MPS VI