Cardiac Involvement in Adult Patients With Fabry Disease; Relation to Enzyme Replacement Therapy

• ClinicalTrials.gov Identifier: NCT02908724
• Recruitment Status: Completed
• First Posted: September 21, 2016
• Last Update Posted: October 16, 2018
• Sponsor: Ulla Feldt-Rasmussen
• Information provided by (Responsible Party): Ulla Feldt-Rasmussen, Rigshospitalet, Denmark

Tracking Information

• First Submitted Date: April 4, 2016
• First Posted Date: September 21, 2016
• Last Update Posted Date: October 16, 2018
• Study Start Date: November 2014
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 17, 2016)

• Left Ventricular Mass Index [ Time Frame: Up to 13 years follow-up ]
  Measured by Transthoracic Echocardiography using a Philips IE 33. Two-dimensional parasternal images were used to determine left ventricular chamber dimensions and wall thickness; LV mass was calculated by the American Society of Echocardiography (ASE) equation and indexed to body surface area. Median [range] is evaluated and presented.
• Left Ventricular Hypertrophy - Sokolow-Lyon voltage criteria [ Time Frame: Up to 13 years follow-up ]
  12-lead electrocardiography (ECG) was performed using a Schiller Cardiovit AT-2 (Schiller AG, Dietikon, Switzerland). Left ventricular hypertrophy was evaluated by Sokolow-Lyon voltage criteria (S in V1 + R in V5/V6 ≥ 35 mm). Median [range] and frequency (%) of hypertrophy is evaluated and presented.
• Left Ventricular Hypertrophy - Cornell voltage product criteria [ Time Frame: Up to 13 years follow-up ]
  12-lead ECG was performed using a Schiller Cardiovit AT-2 (Schiller AG, Dietikon, Switzerland). Left ventricular hypertrophy was evaluated by Cornell product criteria (R in aVL + S in V3 (+6 mm for women) x QRS duration > 2440 mm·ms). Median [range] and frequency (%) of hypertrophy is evaluated and presented.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 17, 2016)

• Clinical outcome [ Time Frame: Up to 13 years follow-up ]
  Cardiac interventions (medication, percutaneous coronary interventions, coronary artery bypass graft, implantation of implantable cardioverter-defibrillators or pacemakers), Cardiac symptoms (Chest pain, palpitations, edema, dyspnea, dizziness, syncope) and all-cause mortality. Frequency (%) is evaluated and presented.
• Arrhythmias [ Time Frame: Up to 13 years follow-up ]
  Atrial fibrillation, atrial flutter, supraventricular tachycardia, non-sustained ventricular tachycardia, measured by ECG and Holter-monitoring. Frequency (%) is evaluated and presented.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cardiac Involvement in Adult Patients With Fabry Disease; Relation to Enzyme Replacement Therapy
• Official Title: Cardiac Involvement in Adult Patients With Fabry Disease; Relation to Enzyme Replacement Therapy - A Nationwide Danish Clinical Cohort Study

Brief Summary

The purpose of this study was to assess the progression of cardiac involvement in adult patients with Fabry Disease (FD), in the unique Danish Fabry cohort and comparing those FD patients receiving primary therapy vs. those that did not.

The hypothesis is, that we will not be able to see a significant positive difference in cardiac involvement in those FD patient who received FD specific therapy vs. those that did not.

Detailed Description

Enzyme replacement therapy and concomitant treatment:

FD specific treatment (ERT, enzyme replacement therapy) have been available since 2001 and patients have been treated with either agalsidase alpha (Replagal®) or agalsidase beta (Fabrazyme®) every other week at recommended doses, 0.2 mg/kg and 1.0 mg/kg, respectively.

Concomitant treatment with cardiovascular medication including angiotensin-converting-enzyme-inhibitor, angiotensin-II-receptor-blocker, acetylsalicylic acid, beta-blocker, calcium-channel-blocker, diuretics and statins, was registered for all patients.

Statistical analysis:

Primarily, we compared the progression of cardiac involvement from baseline to follow-up, according to ERT including subgroup analysis according to gender.

Secondarily, subgroup analysis of the ERT group was performed by separating patients with- and without cardiac disease at baseline, indicated by the presence of myocardial hypertrophy on transthoracic echocardiography (septal thickness or LV posterior wall thickness >0.9 cm for females and >1.0 for males), increased cardiac mass (Left ventricular mass index (LVMi) >95 g/m2 for females and >115g/m2 for males) or systolic dysfunction (ejection fraction <55%) in accordance with the guidelines from the American Society of Echocardiography and the European Association of Echocardiography (Lang et al., 2005).

In these analyses ERT patients' baseline was defined as the last available examination prior to ERT start and follow-up as the last available examination during ERT. Inclusion in the non-ERT group required that patient had not received ERT at study end. Intra-group comparisons of progression from baseline to follow-up were made by McNemar test (categorical variables) and Wilcoxon Signed Rank Test (continuous variables).

Thirdly, for comparisons between treatment groups, linear mixed models were applied on all available data from continuous variables regarding Sokolow-Lyon voltage-, Cornell product ECG criteria and LVMi as no violations of the assumptions for linear mixed model testing were found in initial analyses. The modelling allows for individual difference at a general level (tracking) as well as individual differences in the progression over time, controlled for gender, age at baseline, treatment duration and current ERT status.

Comparisons of major organ involvement at baseline, gene mutations and alfa-galactosidase A activity between treatment groups, were performed by Chi-squared and Mann-Whitney U tests, respectively.

Data from categorical variables are presented as frequency (percentage), and continuous variables are presented as median [range] or estimate (±standard error). Data was analysed using SPSS (version 19.0). All tests were two-sided and a p-value <0.05 was considered statistically significant.

• Study Type: Observational
• Study Design: Observational Model: Cohort; Time Perspective: Retrospective
• Target Follow-Up Duration: Not Provided
• Biospecimen: Not Provided
• Sampling Method: Non-Probability Sample
• Study Population: Sixty-six patients with FD
• Condition: Fabry Disease
• Intervention: Not Provided

Study Groups/Cohorts

• ERT receiving patients
  Patients that were receiving specific treatment for FD (ERT, enzyme replacement therapy, Fabrazyme or Replagal) during the observational time (n= 47).
• non-ERT receiving patients
  Patients that were not receiving specific treatment for FD (ERT, enzyme replacement therapy, Fabrazyme or Replagal) during the observational time (n= 19).

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 17, 2016): 66
• Original Actual Enrollment: Same as current
• Actual Study Completion Date: February 9, 2016
• Actual Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Genetically verified Fabry disease
• Age at baseline >18 years
• Baseline cardiac examination performed

Exclusion Criteria:

• Switch from FD specific treatment (Fabrazyme or Replagal) to no FD specific treatment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT02908724
• Other Study ID Numbers: FAB-ECG
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Ulla Feldt-Rasmussen, Rigshospitalet, Denmark
• Original Responsible Party: Same as current
• Current Study Sponsor: Ulla Feldt-Rasmussen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Ulla Feldt-Rasmussen, MD,DMSc,Prof; Department of Medical Endocrinology

• PRS Account: Rigshospitalet, Denmark
• Verification Date: October 2018