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Trial record 2 of 5 for:    CXCL16

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

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ClinicalTrials.gov Identifier: NCT03632213
Recruitment Status : Recruiting
First Posted : August 15, 2018
Last Update Posted : December 25, 2018
Sponsor:
Collaborator:
The Isaac Foundation
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis IV A Mucopolysaccharidosis VI Mucopolysaccharidoses MPS IV A MPS VI MPS - Mucopolysaccharidosis Morquio A Syndrome Morquio Syndrome A Morquio Syndrome Drug: Losartan Drug: Placebo Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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

Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Clinical Trial to Evaluate the Effects of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI
Actual Study Start Date : November 7, 2018
Estimated Primary Completion Date : February 4, 2020
Estimated Study Completion Date : June 3, 2020


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.




Primary Outcome Measures :
  1. Adverse events related to losartan use [ Time Frame: 12 months ]
    The frequency of adverse events after 12 months will be compared among the groups


Secondary Outcome Measures :
  1. Z score of maximal aortic root diameter measured by Valsalva sinus [ Time Frame: 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.

  2. Changes of serum levels of transforming growth factor (TGF-Beta-1) [ Time Frame: 12 months ]
    Changes of serum levels of transforming growth factor (TGF-Beta-1) between baseline and 12 months

  3. Changes of serum levels of brain-type natriuretic peptide (BNP) [ Time Frame: 12 months ]
    Changes of serum levels of brain-type natriuretic peptide between baseline and 12 months

  4. Changes of serum levels of N-terminal pro b-type natriuretic peptide (NT-ProBNP) [ Time Frame: 12 months ]
    Changes of serum levels of N-terminal pro b-type natriuretic (NT-ProBNP) peptide between baseline and 12 months

  5. Changes of serum levels of creatine kinase-myocardial ban (ck-mb) [ Time Frame: 12 months ]
    Changes of serum levels of creatine kinase-myocardial ban (ck-mb) between baseline and 12 months

  6. Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6) [ Time Frame: 12 months ]
    Changes of serum levels of Chemokine (C-X-C motif) ligand 6 (CXCL6) between baseline and 12 months

  7. Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) [ Time Frame: 12 months ]
    Changes of serum levels of Chemokine (C-X-C motif) ligand 16 (CXCL16) between baseline and 12 months

  8. Changes of serum levels of Endocan-1 (ESM-1) [ Time Frame: 12 months ]
    Changes of serum levels of Endocan-1 (ESM-1) between baseline and 12 months

  9. Changes of serum levels of Placental growth factor (PLGF) [ Time Frame: 12 months ]
    Changes of serum levels ofPlacental growth factor (PLGF) between baseline and 12 months

  10. Changes of serum levels of Fatty acid binding protein 3 (FAPB3) [ Time Frame: 12 months ]
    Changes of serum levels of Fatty acid binding protein 3 (FAPB3) between baseline and 12 months

  11. Changes of serum levels of Fatty acid binding protein 4 (FAPB4) [ Time Frame: 12 months ]
    Changes of serum levels of Fatty acid binding protein 4 (FAPB4) between baseline and 12 months

  12. Changes of serum levels of Oncostatin M [ Time Frame: 12 months ]
    Changes of serum levels of Oncostatin M between baseline and 12 months

  13. Changes of serum levels of Troponin I [ Time Frame: 12 months ]
    Changes of serum levels of Troponin I between baseline and 12 months

  14. Changes of ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months. [ Time Frame: 12 months ]
    Reduction over time in the ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months.

  15. Changes in mitral valve regurgitation [ Time Frame: 12 months ]
    Alteration of the parameter of mitral valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months.

  16. Changes in aortic valve regurgitation [ Time Frame: 12 months ]
    Alteration of the parameter of aortic valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months.

  17. Changes in ejection fraction [ Time Frame: 12 months ]
    Alteration of the ejection fraction measurement as assessed by echocardiography between the baseline and 12 months.

  18. Changes in left ventricular longitudinal strain [ Time Frame: 12 months ]
    Alteration of the measurement of left ventricular longitudinal strain as assessed by echocardiography between the baseline and 12 months.

  19. Changes in E/A ratio [ Time Frame: 12 months ]
    Alteration of the parameter E/A ratio as assessed by echocardiography between the baseline and 12 months .

  20. Changes in E/e' ratio [ Time Frame: 12 months ]
    Alteration of the parameter E/e' ratio as assessed by echocardiography between the baseline and 12 months.


Other Outcome Measures:
  1. Glycosaminoglycan after 6 months [ Time Frame: 6 months ]
    Difference in urinary glycosaminoglycan levels after 6 months

  2. Glycosaminoglycan after 12 months [ Time Frame: 12 months ]
    Difference in urinary glycosaminoglycan levels after 12 months



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   10 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 6 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 , beta-blocker or calcium channel blocker
  • Patients with previous adverse events related to treatment with losartan or contraindication to this treatment (Table 2).
  • Inability, in the opinion of the investigator, to complete the study procedures.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03632213


Contacts
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Contact: Diane Pedrini, RN +555133596340 dpedrini@hcpa.edu.br
Contact: Fabiano Poswar, MD +555133596340 fposwar@hcpa.edu.br

Locations
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Brazil
Hospital de Clinicas de Porto Alegre Recruiting
Porto Alegre, Rio Grande Do Sul, Brazil, 90035-903
Contact: Diane Pedrini, RN    +55 51 33596340    dpedrini@hcpa.edu.br   
Contact: Fabiano Poswar, MD    +55 51 33596340    fposwar@hcpa.edu.br   
Principal Investigator: Roberto Giugliani, MD, PhD         
Sponsors and Collaborators
Hospital de Clinicas de Porto Alegre
The Isaac Foundation
Investigators
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Principal Investigator: Roberto Giugliani, MD, PhD Hospital de Clinicas de Porto Alegre
Study Director: Guilherme Baldo, PhD Hospital de Clinicas de Porto Algre

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Responsible Party: Hospital de Clinicas de Porto Alegre
ClinicalTrials.gov Identifier: NCT03632213     History of Changes
Other Study ID Numbers: 17-0685
First Posted: August 15, 2018    Key Record Dates
Last Update Posted: December 25, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Hospital de Clinicas de Porto Alegre:
Mucopolysaccharidoses
Losartan
Aortic root dilatation
Echocardiogram
MPS IV
MPS VI

Additional relevant MeSH terms:
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Syndrome
Cardiovascular Diseases
Mucopolysaccharidoses
Mucopolysaccharidosis IV
Osteochondrodysplasias
Mucopolysaccharidosis VI
Disease
Pathologic Processes
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases
Bone Diseases, Developmental
Bone Diseases
Musculoskeletal Diseases
Losartan
Anti-Arrhythmia Agents
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action