Canadian Fabry

CFDI STUDY with ENZYME REPLACE THERAPY (ERT): Canada-Wide Patient Recruitment

Fabry disease is a rare, inherited, genetic condition due to a deficiency of an enzyme called alpha-galactosidase A. This enzyme deficiency causes the small blood vessels to accumulate a substance called glycolipid. Without sufficient levels of the enzyme, alpha-galactosidase A, persons with Fabry Disease develop severe neuropathic pain, kidney disease, heart disease, stroke and/or premature death; often before the age of 60 years old.

Fabry Disease is estimated to affect approximately one out of every 40,000 males and up to twice as many females in Canada. We know there are approximately 225 people living in Canada with Fabry disease, with the largest number living in Nova Scotia. However, we do not have the exact number of persons in Canada who have this disease. A common problem in studying rare conditions is the difficulty in identifying the majority of people suffering from such a disease. Gathering their health information in order to better understand the natural disease progression and its response to treatment is difficult.

Until recently, treating symptoms was all that was available for people with Fabry Disease. In 2001, enzyme replacement therapy (ERT) was developed as a treatment for this rare condition. ERT provides the deficient enzyme and may be beneficial in Fabry Disease. The Canadian Fabry Disease Initiative (CFDI) will determine the impact of Enzyme Replacement Therapy (ERT) on the development of complications of Fabry Disease in males and females currently on, or who have received ERT; and to assess which of these complications respond to the ERT therapy. Another purpose of this study is to establish a national registry which will collect information on all persons with Fabry Disease in Canada.

Early ERT studies involving humans had small numbers of subjects and the studies were of short duration. The results of these clinical studies did lead to approval of the therapy in many countries around the world including Canada. To date though, evidence of the usefulness of ERT and its direct impact on the natural course of Fabry disease has been limited, while its cost continues to be very high. As a result of these issues, there will need to be continued and long-term collection of information related to the effectiveness of ERT to better document its true clinical outcomes in Canadian people with Fabry disease.

The 5 goals of this nation-wide study are as follows:

1. To establish a national registry which will collect information related to the identification and monitoring of all persons with Fabry disease in Canada;
2. To determine the degree to which existing complications of Fabry disease respond or fail to respond to ERT;
3. To determine the impact of ERT on the development of complications of Fabry disease in men and women who are on ERT or whose ERT was interrupted;
4. To identify which of these clinical problems can best predict the outcome of ERT on Fabry disease.
5. To identify possible side effects of ERT.

CFDI STUDY with ENZYME REPLACE THERAPY (ERT): Canada-Wide Patient Recruitment

There are approximately 250 people in Canada known to have Fabry Disease For more details about Fabry Disease, please refer to the "Brief Summary." The Canadian Fabry Disease Initiative will collect information from 3 different study groups of Fabry subjects recruited from across Canada over a 10-year period.

The 5 goals of this nation-wide study are as follows:

1. To establish a national registry which will collect information related to the identification and monitoring of all persons with Fabry disease in Canada;
2. To determine the degree to which existing complications of Fabry disease respond or fail to respond to ERT;
3. To determine the impact of ERT on the development of complications of Fabry disease in men and women who are on ERT or whose ERT was interrupted;
4. To identify which of these clinical problems can best predict the outcome of ERT on Fabry disease.
5. To identify possible side effects of ERT.

This 3-armed study will consist of 3 study populations. The first group will be referred to as Cohort 1A. This group includes males and females with Fabry Disease, who are currently on ERT or have had ERT treatment interrupted. We are expecting approximately 50 persons in Cohort 1A in total.

The second group, Cohort 1B, will consist of people who have never had ERT, but who now meet the current Canadian guidelines for starting ERT therapy. Approximately 100 subjects will be recruited in Canada.

The third group will be called the Natural History Cohort with approximately 100 Canadian subjects with mild Fabry Disease who currently do not need ERT. For BC, we anticipate recruiting 15 subjects for the Natural History Cohort group. All these numbers are estimates because the exact number of people in Canada with Fabry Disease is unknown at this time.

Data will be collected at baseline and every 6 months for 3 years, as follows:

• Medical History
• Physical examination
• Neurological exam
• Eye exam
• Electrocardiogram (ECG) - an electrical tracing of one's heart rhythm
• Echocardiogram (ultrasound of the heart)
• Holter monitor
• Audiogram
• Magnetic Resonance Imaging (MRI) or CT Scan of the head
• Pain Questionnaire and a Quality of Life Questionnaire
• Lab tests (including alpha-galactosidase levels)
• Review of current medications
• 24-hour urine collection or a random spot urine test

To date though, evidence of the usefulness of ERT and its direct impact on the natural course of Fabry disease has been limited, while its cost continues to be very high (approximately $300,000 CDN per year per patient). As a result of these issues, there will need to be continued and long-term collection of information related to the effectiveness of ERT to better document its true clinical outcomes in Canadian people with Fabry disease.

INCLUSION CRITERIA:

(A) ALL of the following criteria must be met for each CFDI subject in Cohort 1A, Cohort 1B & the Natural History Cohort:

• Age 5 years and older, up to & including age 85 years; and
• Able to give informed consent; and
• A clinical diagnosis of Fabry disease; and
• Compliance with all the clinic visits, questionnaires, interviews and assessments during the study period; and
• A Canadian citizen or a landed immigrant For Cohort 1A and Cohort 1B, each subject must also be able to tolerate Enzyme Replacement Therapy (ERT)

(B) ALL of the following criteria must be met for each REP001A subject originally enroled as a CFDI Cohort 1A or Cohort 1B subject:

• Age 5-85 years old; and
• Able to give informed consent; and
• A clinical diagnosis of Fabry disease; and
• Willing to comply with all the clinic visits, questionnaires, interviews and assessments during the study period; and
• A Canadian citizen or a landed immigrant; and
• Receiving agalsidase alfa (Replagal®) standard doses (0.2 mg/kg every 2 weeks) for a minimum of 6 consecutive months; and
• Evidence of declining kidney and/or heart function while on Replagal®, as shown by laboratory and/or imaging results; and
• Currently enrolled in the CFDI study.

EXCLUSION CRITERIA:

• Intolerance to ERT, such as a serious drug reaction; or
• Enrolment in another clinical study in the last 30 days; or
• Problem complying with all the clinic visits, questionnaires, interviews and assessments during the study period; or
• An estimated life expectancy of less than 12 months; and
• For REP001A (high dose Replagal sub-study): worsening of kidney and/or heart function (as shown by laboratory and/or imaging results) due to another underlying medical condition (i.e. not related to Fabry Disease)