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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Mucopolysaccharidoses; Mucopolysaccharidosis VI; Morquio A Syndrome; Mucopolysaccharidosis IV A; MPS IV A; MPS VI; MPS - Mucopolysaccharidosis; Morquio Syndrome A; Morquio Syndrome
• Intervention / Treatment: Drug: Losartan; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Diane Pedrini, RN; Phone Number: +555133596340; Email: dpedrini@hcpa.edu.br
• Study Contact Backup: Name: Fabiano Poswar, MD; Phone Number: +555133596340; Email: fposwar@hcpa.edu.br

Study Locations

• Brazil
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
      • Hospital de Clinicas de Porto Alegre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 38 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Glycosaminoglycan after 6 months	Difference in urinary glycosaminoglycan levels after 6 months	6 months
Glycosaminoglycan after 12 months	Difference in urinary glycosaminoglycan levels after 12 months	12 months

Collaborators and Investigators

• Sponsor: Hospital de Clinicas de Porto Alegre
• Collaborators: The Isaac Foundation
• Investigators: Principal Investigator: Roberto Giugliani, MD, PhD, Hospital de Clinicas de Porto Alegre; Study Director: Guilherme Baldo, PhD, Hospital de Clinicas de Porto Algre

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2018
• Primary Completion (Anticipated): May 4, 2023
• Study Completion (Anticipated): August 3, 2023

Study Registration Dates

• First Submitted: August 3, 2018
• First Submitted That Met QC Criteria: August 14, 2018
• First Posted (Actual): August 15, 2018

Study Record Updates

• Last Update Posted (Actual): December 19, 2022
• Last Update Submitted That Met QC Criteria: December 15, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: MPS VI; Echocardiogram; Losartan; Mucopolysaccharidoses; Aortic root dilatation; MPS IV
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Genetic Diseases, Inborn; Musculoskeletal Diseases; Connective Tissue Diseases; Bone Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Bone Diseases, Developmental; Cardiovascular Diseases; Syndrome; Mucopolysaccharidoses; Osteochondrodysplasias; Mucopolysaccharidosis IV; Mucopolysaccharidosis VI; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Losartan
• Other Study ID Numbers: 17-0685

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No