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

Phase 2

Active, not recruiting

• Conditions: Mucopolysaccharidosis IV A; Mucopolysaccharidoses; MPS IV A; MPS VI; Mucopolysaccharidosis VI; MPS - Mucopolysaccharidosis; Morquio A Syndrome; Morquio Syndrome A; Morquio Syndrome
• Interventions: Drug: Losartan; Drug: Placebo

• Registration Number: NCT03632213
• Lead Sponsor: Hospital de Clinicas de Porto Alegre

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.

Study Timeline

• Study First Submitted: 2018-08-03
• Study First Submitted QC: 2018-08-14
• Study First Posted: 2018-08-15
• Study Start: 2018-11-07
• Status Verified: 2022-12
• Last Update Submitted: 2022-12-15
• Last Update Posted: 2022-12-19
• Primary Completion: 2023-05-04
• Study Completion: 2023-08-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 10

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Losartan	Losartan	Losartan group: 15 patients, both sexes, will receive Losartan 0.4 to 1.4 mg/kg/day orally for 12 months.
Placebo	Placebo	Placebo group:15 patients, both sexes, will receive oral placebo for 12 months.

Primary Outcome Measures

Name	Time	Method
Adverse events related to losartan use	12 months	The frequency of adverse events after 12 months will be compared among the groups

Secondary Outcome Measures

Name	Time	Method
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 transforming growth factor (TGF-Beta-1)	12 months	Changes of serum levels of transforming growth factor (TGF-Beta-1) 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 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 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 Oncostatin M	12 months	Changes of serum levels of Oncostatin M 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.
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.

Trial Locations

Locations (1)

Hospital de Clinicas de Porto Alegre; 🇧🇷 Porto Alegre, Rio Grande Do Sul, Brazil