Safety and Efficacy Study of Several Replagal Dosing Regimens on Cardiac Function in Adults With Fabry Disease

A Multi-Center, Open-Label, Randomized Study Evaluating the Safety and Efficacy of Three Dosing Regimens of Replagal Enzyme Replacement Therapy in Adult Patients With Fabry Disease

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00864851

Enrollment

Registered

2009-03-19

Start date

2008-12-29

Completion date

2012-07-05

Last updated

2021-06-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Fabry Disease

Brief summary

The purpose of this study is to compare the safety and effectiveness of various doses of Replagal in patients with cardiomyopathy due to Fabry disease.

Detailed description

Fabry disease is an inherited, metabolic disease caused by mutations in the GALA gene. Patients with Fabry disease accumulate a complex glycosphingolipid named globotriaosylceramide (Gb3) in various tissues and organs. All organs are affected in Fabry disease but the majority of the morbidity and mortality are caused by cardiac, renal and neurological dysfunction. Accumulation of Gb3 in the heart causes hypertrophic cardiomyopathy, valvular abnormalities, arrhythmias and infarctions. Replagal has been shown to reduce Gb3 from key tissues and organs, and stabilize renal function in patients with Fabry disease. Evidence suggests that Replagal reduces left ventricular mass (LVM) and improves midwall fractional shortening (MFS) of the heart. Left ventricular hypertrophy is a major cause of morbidity and mortality in patients with Fabry disease. This is a study of the safety and effectiveness of 3 dosing regimens of Replagal in adult patients with left ventricular hypertrophy due to Fabry disease. The primary objective of the study is to compare the effects of 2 dosing regimens of Replagal (0.2 mg/kg IV every other week and 0.2 mg/kg IV weekly) on the reduction of left ventricular mass as measured by echocardiography. The secondary objectives of this study are to compare the effects of 2 dosing regimens of Replagal (0.2 mg/kg IV every other week and 0.2 mg/kg IV weekly) on each of the following: exercise tolerance; improvement in disease-specific quality of life in heart failure patients; improvement of heart failure symptoms; magnitude of reduction in Gb3; rate of decline in renal function and improvement in the severity of proteinuria/albuminuria; and safety. An alternative treatment regimen of 0.4 mg/kg Replagal IV weekly will also be explored but without formal comparison to the 0.2 mg/kg regimens. The investigation of the safety and efficacy of the 0.4 mg/kg IV weekly regimen is a secondary objective of this study.

Interventions

BIOLOGICALReplagal

Intravenous (IV) infusion for 12 months

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* \>18 years-old; * Male:Fabry disease confirmed by deficiency of alfa galactosidase A activity OR Female:Fabry disease confirmed by a mutation of the alfa galactosidase A gene; * ERT-naïve; * LVM/h \> 50g/m2.7 for males and \>47 g/m2.7 for females; * Negative pregnancy test at enrollment and contraception use required throughout study for female patients; * Signed informed consent;

Exclusion criteria

* Class IV heart failure; * Clinically significant hypertension; * Hemodynamically significant valvular stenosis or regurgitation; * Morbid obesity; * Known autosomal dominant sarcoplasmic contractile protein gene mutation; * Treatment with any investigational drug or device within the 30 days; * Unable to comply with the protocol as determined by the Investigator; * Positive for hepatitis B, hepatitis C or HIV

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline to Month 12 in Left Ventricular Mass Indexed to Height (LVMI)	Baseline, Month 12 (Week 53)	Left ventricular mass (LVM) was measured through echocardiography.

Secondary

Measure	Time frame	Description
Change From Baseline to Month 12 in Distance Walked in 6-Minute Walk Test (6MWT)	Baseline, Month 12 (Week 53)	Exercise tolerance using the 6MWT was measured as the total distance walked in 6 minutes.
Change From Baseline to Month 12 in the Minnesota Living With Heart Failure Questionnaire (MLHF-Q) Summary Score	Baseline, Month 12 (Week 53)	Quality of life (QoL) was evaluated using the MLHF-Q, version 2. The questionnaire is designed to assess the degree to which heart failure symptoms affect a patient's daily life. The summary score ranges from 0 to 105, with a score of 105 representing the highest adverse impact on a patient's QoL.
Change From Baseline to Month 12 in New York Heart Association (NYHA) Functional Class	Baseline, Month 12 (Week 53)	The NYHA functional classification system relates symptoms to everyday activities and the patient's quality of life. NYHA Classification - The Stages of Heart Failure: Class I (Mild): No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath). Class II (Mild): Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea. Class III (Moderate): Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea. Class IV (Severe): Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.
Change From Baseline to Month 12 in Maximal Oxygen Consumption (VO2 Max) at Peak Exercise	Baseline, Month 12 (Week 53)	Exercise tolerance as measured by VO2 max at peak exercise using the standard exponential exercise protocol (STEEP).
Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR)	Baseline, Month 12 (Week 53)	Renal function was assessed by an evaluation of change from baseline to Month 12 in eGFR as calculated using the Modification of Diet for Renal Disease (MDRD) equation.
Change From Baseline to Month 12 in Urinary Albumin/Creatinine (A/Cr) Ratio	Baseline, Month 12 (Week 53)	—
Safety Evaluation	56 Weeks	Adverse events were collected throughout the study, from the time of informed consent to approximately 30 days post-final infusion.
Change From Baseline to Month 12 in Plasma Globotriaosylceramide (GB3)	Baseline, Month 12 (Week 53)	—

Countries

Australia, Czechia, Finland, Paraguay, Poland, Slovenia, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
Replagal 0.2 mg/kg, IV, Every Other Week Patients who received Replagal 0.2 mg/kg via intravenous infusion every other week for 52 weeks.	20
Replagal 0.2 mg/kg, IV, Weekly Patients who received Replagal 0.2 mg/kg via intravenous infusion every week for 52 weeks.	19
Replagal 0.4 mg/kg, IV, Weekly Patients who received Replagal 0.4 mg/kg via intravenous infusion every week for 52 weeks.	5
Total	44

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Death	1	0
Overall Study	Patient uncooperative	1	0
Overall Study	Physician Decision	1	0
Overall Study	Withdrawal by Subject	0	1

Baseline characteristics

Characteristic	Replagal 0.2 mg/kg, IV, Weekly	Total	Replagal 0.2 mg/kg, IV, Every Other Week	Replagal 0.4 mg/kg, IV, Weekly
Age, Continuous	51.8 years STANDARD_DEVIATION 11.42	50.8 years STANDARD_DEVIATION 9.34	50.3 years STANDARD_DEVIATION 7.23	49.4 years STANDARD_DEVIATION 9.75
Age, Customized 18 to <45 years	6 Participants	12 Participants	5 Participants	1 Participants
Age, Customized >=45 years	13 Participants	32 Participants	15 Participants	4 Participants
Baseline Distance Walked in 6-Minute Walk Test (6MWT)	514.3 m STANDARD_DEVIATION 87.3	492.8 m STANDARD_DEVIATION 97	459.6 m STANDARD_DEVIATION 103	530.7 m STANDARD_DEVIATION 90.2
Baseline Estimated Glomerular Filtration Rate (eGFR)	78.1 mL/min/1.73 m^2 STANDARD_DEVIATION 33.8	79.2 mL/min/1.73 m^2 STANDARD_DEVIATION 33.1	82.0 mL/min/1.73 m^2 STANDARD_DEVIATION 34.1	72.1 mL/min/1.73 m^2 STANDARD_DEVIATION 31.2
Baseline Left Ventricular Mass Indexed to Height (LVMI)	82.6 g/m^2.7 STANDARD_DEVIATION 28.3	81.5 g/m^2.7 STANDARD_DEVIATION 28.5	76.1 g/m^2.7 STANDARD_DEVIATION 22.8	99.3 g/m^2.7 STANDARD_DEVIATION 46.2
Baseline Maximal Oxygen Consumption (VO2 max) at Peak Exercise	22.6 mL/min/kg STANDARD_DEVIATION 6.89	21.6 mL/min/kg STANDARD_DEVIATION 7.05	20.2 mL/min/kg STANDARD_DEVIATION 6.2	24.0 mL/min/kg STANDARD_DEVIATION 11.69
Baseline Minnesota Living with Heart Failure Questionnaire (MLHF-Q) Summary Score	21.1 scores on a scale STANDARD_DEVIATION 21	28.1 scores on a scale STANDARD_DEVIATION 23.8	37.0 scores on a scale STANDARD_DEVIATION 23.8	19.6 scores on a scale STANDARD_DEVIATION 26.5
Baseline New York Heart Association (NYHA) Functional Class Class I	10 Participants	18 Participants	6 Participants	2 Participants
Baseline New York Heart Association (NYHA) Functional Class Class II	9 Participants	22 Participants	11 Participants	2 Participants
Baseline New York Heart Association (NYHA) Functional Class Class III	0 Participants	4 Participants	3 Participants	1 Participants
Baseline New York Heart Association (NYHA) Functional Class Class IV	0 Participants	0 Participants	0 Participants	0 Participants
Baseline Plasma Globotriaosylceramide (GB3)	5.652 nmol/ml STANDARD_DEVIATION 5.212	5.800 nmol/ml STANDARD_DEVIATION 4.104	6.067 nmol/ml STANDARD_DEVIATION 3.388	5.292 nmol/ml STANDARD_DEVIATION 1.865
Baseline Urinary Albumin/Creatinine (A/Cr) Ratio	293.4 mg/g STANDARD_DEVIATION 521.23	303.0 mg/g STANDARD_DEVIATION 532.27	313.4 mg/g STANDARD_DEVIATION 614.07	298.2 mg/g STANDARD_DEVIATION 175.85
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	2 Participants	1 Participants	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants	42 Participants	19 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	19 Participants	44 Participants	20 Participants	5 Participants
Sex: Female, Male Female	9 Participants	18 Participants	6 Participants	3 Participants
Sex: Female, Male Male	10 Participants	26 Participants	14 Participants	2 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	19 / 20	17 / 19	5 / 5	41 / 44
serious Total, serious adverse events	8 / 20	5 / 19	2 / 5	15 / 44