A Multicenter Open-Label Treatment Protocol to Observe the Safety of Replagal (Agalsidase Alfa) Enzyme Replacement Therapy in Canadian Patients With Fabry Disease

A Multicenter Open-Label Treatment Protocol to Observe the Safety of Replagal® (Agalsidase Alfa) Enzyme Replacement Therapy in Canadian Patients With Fabry Disease

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01298141

Enrollment

171

Registered

2011-02-17

Start date

2011-08-10

Completion date

2017-09-25

Last updated

2021-06-08

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

Conditions

Fabry Disease

Keywords

Replagal, Enzyme Replacement Therapy, agalsidase alfa

Brief summary

The purpose of this study is to observe the safety of agalsidase alfa in Canadian patients with Fabry disease.

Detailed description

This study will evaluate the safety of agalsidase alfa in patients with Fabry disease. Patients diagnosed with Fabry disease who meet current Canadian guidelines for enzyme replacement therapy will be eligible to enroll in the study and will receive agalsidase alfa at a dose of 0.2 mg/kg body weight administered by an IV infusion over 40 minutes every week or every other week, based on previous treatment. Shire has implemented a change to the drug substance manufacturing process. Safety data will be collected in patients receiving product manufactured with this process. There are no changes to the drug product formulation, manufacturing site, manufacturing process, and container closure.

Interventions

BIOLOGICALagalsidase alfa

Cohort 1: 0.2 mg/kg body weight administered as an intravenous (IV) infusion over 40 minutes every other week (EOW) Cohort 2: 0.2 mg/kg body weight administered as an intravenous (IV) infusion over 40 minutes weekly

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

Inclusion criteria

Cohort 1: 1. The patient has a documented diagnosis of Fabry disease. 2. The patient is sufficiently compliant with study activities to participate in this treatment plan, as judged by the Investigator. 3. The patient must meet current Canadian guidelines for enzyme replacement therapy for Fabry disease by meeting one of the following criteria: 1. Age-adjusted glomerular filtration rate (GFR) \<80 ml/min or a decline in GFR of \>10% which is sustained for 3 months and for which other causes of declining renal function have been excluded by a nephrologist or any 2 of the following: * Isolated proteinuria ≥500 mg/day/1.73 m2 without other cause * Nephrogenic diabetes insipidus * Fanconi syndrome * Hypertension 2. Evidence of cardiac involvement related to Fabry disease including any 2 of the following: * Left ventricular (LV) wall thickness \>12 mm * Left ventricular hypertrophy (LVH) by electrocardiogram (ECG); Estes ECG score must be \>5 * Left ventricular mass index (LVMI) by 2D echocardiogram 20% above normal for age * Diastolic filling abnormalities by 2D echocardiogram or by other accepted measures of diastolic filling. E/A ration \>2.0 and deceleration time \<140 msec * Increase of LV mass of at least 5 g/m2/year, with three measurements over a minimum of 12 months * Increase of left atrium (LA) size on 2D echo at least 10% above normal for age. In parasternal long axis view (PLAX) \>33 mm; in four chamber view \>42 mm * Cardiac conduction and rhythm abnormalities: atrioventricular (AV) block, short PR interval, left branch bundle block (LBBB), ventricular or atrial tachyarrhythmias, sinus bradycardia (in the absence of drugs with negative chronotropic activity) * Delayed posterolateral left ventricular wall late enhancement on MRI as evidence of advanced cardiac disease with fibrosis 3. Evidence of neurological involvement related to Fabry disease including 1 of the following: * Stroke or transient ischemic attack (TIA) prior to the age of 55 documented by a neurologist * Acute onset unilateral hearing loss * Acut monocular visual loss without other cause 4. Chronic, intractable diarrhea and/or abdominal pain/cramps, refractory to standard management for at least 6 months. 5. Chronic, intractable neuropathic pain, refractory to analgesics and standard pain management for at least 6 months. Cohort 2: 4. Patient must have participated in Study REP001a.

Exclusion criteria

1. The patient has experienced an anaphylactic or anaphylactoid reaction or other infusion-related reaction which, in the opinion of the Investigator, precludes further treatment with agalsidase alfa or may interfere with the interpretation of the study. 2. The patient is otherwise unsuitable for the study, in the opinion of the Investigator. 3. The patient is enrolled in another clinical study, other than the Canadian Fabry Disease Initiative (CFDI).

Design outcomes

Primary

Measure	Time frame	Description
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From the start of study treatment up to 30 days after the last dose of study drug administration (up to 320 weeks)	An adverse event (AE) was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered investigational product-related.Treatment-emergent adverse events (TEAEs) were defined as those events which occurred or worsened in severity after first treatment with Replagal AF until 30 days after the last dose. A serious AE (SAE) was any AE occurred at any dose that resulted in death, life-threatening, hospitalization, prolongation of existing hospitalization, persistent or significant disability or incapacity and congenital anomaly or birth defect.
Number of Participants With Infusion-Related Reactions (IRR)	From the start of study treatment up to 30 days after the last dose of study drug administration (up to 320 weeks)	An IRR (also referred to as infusion-related adverse event \[IRAE\]) was defined as an AE that began either during the infusion or within 12 hours after the start of the infusion and was judged as possibly or probably related to study drug. The IRRs were classified based on the severity as Mild=No limitation of usual activities, Moderate=Some limitation of usual activities, Severe=Inability to carry out usual activities and Life-threatening=Immediate risk of death. The number of participants with infusion-related reactions was reported.
Number of Participants Who Reported Positive to Immunoglobulin A (IgA)	Baseline (within 6 months prior to first dose) up to Week 129	The IgA status was measured using enzyme-linked immunosorbent assay (ELISA). Number of participants who reported positive to IgA was reported.
Number of Participants Who Reported Positive to Immunoglobulin E (IgE)	Baseline (within 6 months prior to first dose) up to Week 129	The IgE status was measured using ELISA. Number of participants who reported positive to IgE was reported.
Number of Participants Who Reported Positive to Immunoglobulin M (IgM)	Baseline (within 6 months prior to first dose) up to Week 129	The IgM status was measured using ELISA. Number of participants who reported positive to IgM was reported.
Number of Participants Who Reported Positive to Anti-drug Antibody (ADA)	Baseline (within 6 months prior to first dose) up to Week 285	The ADA status was measured using ELISA and electrochemiluminescent (ECL) immunoassay. Number of participants who reported positive to ADA was reported.
Number of Participants Who Reported Positive to Neutralizing Antibody (NAb)	Baseline (within 6 months prior to first dose) up to Week 285	The NAb status was measured using enzyme activity inhibition assay. Number of participants who reported positive to NAb was reported.

Countries

Canada

Participant flow

Recruitment details

This multicenter study was conducted at 12 sites in Canada between 10 Aug 2011 (first participant first visit) and 25 Sep 2017 (last participant last visit).

Pre-assignment details

A total of 171 participants enrolled into cohort 1 (participants from Canadian Fabry Disease Initiative \[CFDI\]) and cohort 2 (participants who participated in study REP001a) and among them 167 participants received at least one full or partial dose of Replagal (agalsidase alfa) animal free (AF).

Participants by arm

Arm	Count
Replagal (Agalsidase Alfa) Participants in cohort 1 received Replagal AF IV infusion at a dose of 0.2 mg/kg body weight EOW and cohort 2 received Replagal AF IV infusion at a dose of 0.2 mg/kg body weight weekly until the drug became commercially available or the participant discontinued, whichever came first.	167
Total	167

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	3
Overall Study	Death	6
Overall Study	Lost to Follow-up	1
Overall Study	Not treated	4
Overall Study	Other	5
Overall Study	Refusal of Required Study Procedures	1
Overall Study	Termination of Study by the Investigator	5
Overall Study	Withdrawal by Subject	6

Baseline characteristics

Characteristic	Replagal (Agalsidase Alfa)
Age, Continuous	48.85 Years STANDARD_DEVIATION 14.821
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	165 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	5 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	160 Participants
Sex: Female, Male Female	76 Participants
Sex: Female, Male Male	91 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	6 / 167
other Total, other adverse events	160 / 167
serious Total, serious adverse events	74 / 167

Outcome results

Primary

Number of Participants Who Reported Positive to Anti-drug Antibody (ADA)

The ADA status was measured using ELISA and electrochemiluminescent (ECL) immunoassay. Number of participants who reported positive to ADA was reported.

Time frame: Baseline (within 6 months prior to first dose) up to Week 285