Morquio A Syndrome, Morquio Syndrome, Morquio Syndrome A, MPS IV A, MPS - Mucopolysaccharidosis, MPS VI, Mucopolysaccharidoses, Mucopolysaccharidosis IV A, Mucopolysaccharidosis VI
Conditions
Keywords
Mucopolysaccharidoses, Losartan, Aortic root dilatation, Echocardiogram, MPS IV, MPS VI
Brief summary
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
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.
Interventions
DRUGLosartan
Losartan group: 15 patients, both sexes, will receive Losartan 0.4 to 1.4 mg/kg/day orally for 12 months.
DRUGPlacebo
Placebo group: 15 patients, both sexes, will receive oral placebo for 12 months.
Sponsors
The Isaac Foundation
Hospital de Clinicas de Porto Alegre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Intervention 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
Eligibility
Sex/Gender
ALL
Age
10 Years to 40 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse events related to losartan use | 12 months | The frequency of adverse events after 12 months will be compared among the groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes of serum levels of Oncostatin M | 12 months | Changes of serum levels of Oncostatin M between baseline and 12 months |
| Z score of maximal aortic root diameter measured by Valsalva sinus | 12 months | 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. |
| Changes of serum levels of transforming growth factor (TGF-Beta-1) | 12 months | Changes of serum levels of transforming growth factor (TGF-Beta-1) between baseline and 12 months |
| Changes of serum levels of brain-type natriuretic peptide (BNP) | 12 months | Changes of serum levels of brain-type natriuretic peptide between baseline and 12 months |
| Changes of serum levels of N-terminal pro b-type natriuretic peptide (NT-ProBNP) | 12 months | Changes of serum levels of N-terminal pro b-type natriuretic (NT-ProBNP) peptide between baseline and 12 months |
| Changes of serum levels of creatine kinase-myocardial ban (ck-mb) | 12 months | Changes of serum levels of creatine kinase-myocardial ban (ck-mb) between baseline and 12 months |
| Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6) | 12 months | Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6) between baseline and 12 months |
| Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) | 12 months | Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) between baseline and 12 months |
| Changes of serum levels of Endocan-1 (ESM-1) | 12 months | Changes of serum levels of Endocan-1 (ESM-1) between baseline and 12 months |
| Changes of serum levels of Placental growth factor (PLGF) | 12 months | Changes of serum levels ofPlacental growth factor (PLGF) between baseline and 12 months |
| Changes in E/A ratio | 12 months | Alteration of the parameter E/A ratio as assessed by echocardiography between the baseline and 12 months . |
| Changes in E/e' ratio | 12 months | Alteration of the parameter E/e' ratio as assessed by echocardiography between the baseline and 12 months. |
| Changes of serum levels of Fatty acid binding protein 3 (FAPB3) | 12 months | Changes of serum levels of Fatty acid binding protein 3 (FAPB3) between baseline and 12 months |
| Changes of serum levels of Fatty acid binding protein 4 (FAPB4) | 12 months | Changes of serum levels of Fatty acid binding protein 4 (FAPB4) between baseline and 12 months |
| Changes of serum levels of Troponin I | 12 months | Changes of serum levels of Troponin I between baseline and 12 months |
| Changes of ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months. | 12 months | Reduction over time in the ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months. |
| Changes in mitral valve regurgitation | 12 months | Alteration of the parameter of mitral valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months. |
| Changes in aortic valve regurgitation | 12 months | Alteration of the parameter of aortic valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months. |
| Changes in ejection fraction | 12 months | Alteration of the ejection fraction measurement as assessed by echocardiography between the baseline and 12 months. |
| Changes in left ventricular longitudinal strain | 12 months | Alteration of the measurement of left ventricular longitudinal strain as assessed by echocardiography between the baseline and 12 months. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Glycosaminoglycan after 6 months | 6 months | Difference in urinary glycosaminoglycan levels after 6 months |
| Glycosaminoglycan after 12 months | 12 months | Difference in urinary glycosaminoglycan levels after 12 months |
Countries
Brazil
Outcome results
None listed