Clinical trial NCT03632213: Evaluation of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI
Official title: A Randomized Clinical Trial to Evaluate the Effects of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Mucopolysaccharidosis IV A
Mucopolysaccharidosis VI
Mucopolysaccharidoses
MPS IV A
MPS VI
MPS - Mucopolysaccharidosis
Morquio A Syndrome
Morquio Syndrome A
Morquio Syndrome
Keywords: Mucopolysaccharidoses
Losartan
Aortic root dilatation
Echocardiogram
MPS IV
MPS VI
Lead sponsor: Hospital de Clinicas de Porto Alegre
Sponsor class: OTHER
Collaborators: name: The Isaac Foundation
First posted: 2018-08-15
Enrollment: 10
Sex: ALL
Minimum age (years): 10
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Adverse events related to losartan use
timeFrame: 12 months
Secondary outcomes:
measure: Z score of maximal aortic root diameter measured by Valsalva sinus
timeFrame: 12 months
measure: Changes of serum levels of transforming growth factor (TGF-Beta-1)
timeFrame: 12 months
measure: Changes of serum levels of brain-type natriuretic peptide (BNP)
timeFrame: 12 months
measure: Changes of serum levels of N-terminal pro b-type natriuretic peptide (NT-ProBNP)
timeFrame: 12 months
measure: Changes of serum levels of creatine kinase-myocardial ban (ck-mb)
timeFrame: 12 months
measure: Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6)
timeFrame: 12 months
measure: Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16)
timeFrame: 12 months
measure: Changes of serum levels of Endocan-1 (ESM-1)
timeFrame: 12 months
measure: Changes of serum levels of Placental growth factor (PLGF)
timeFrame: 12 months
measure: Changes of serum levels of Fatty acid binding protein 3 (FAPB3)
timeFrame: 12 months
measure: Changes of serum levels of Fatty acid binding protein 4 (FAPB4)
timeFrame: 12 months
measure: Changes of serum levels of Oncostatin M
timeFrame: 12 months
measure: Changes of serum levels of Troponin I
timeFrame: 12 months
measure: Changes of ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months.
timeFrame: 12 months
measure: Changes in mitral valve regurgitation
timeFrame: 12 months
measure: Changes in aortic valve regurgitation
timeFrame: 12 months
measure: Changes in ejection fraction
timeFrame: 12 months
measure: Changes in left ventricular longitudinal strain
timeFrame: 12 months
measure: Changes in E/A ratio
timeFrame: 12 months
measure: Changes in E/e' ratio
timeFrame: 12 months
Other outcomes:
measure: Glycosaminoglycan after 6 months
timeFrame: 6 months
measure: Glycosaminoglycan after 12 months
timeFrame: 12 months
Locations:
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
state: Rio Grande Do Sul
Study officials:
affiliation: Hospital de Clinicas de Porto Alegre
name: Roberto Giugliani, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hospital de Clinicas de Porto Algre
name: Guilherme Baldo, PhD
role: STUDY_DIRECTOR
References: