Efficacy and Safety Study of Velaglucerase Alfa in Children and Adolescents With Type 3 Gaucher Disease

Study Overview
=================
Brief Summary
-----------------
Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of the enzyme glucocerebrosidase (GCB). Gaucher disease has been classified into 3 clinical subtypes based on the presence or absence of neurological symptoms and the severity of these neurological symptoms. Patients with type 2 Gaucher disease present with acute neurological deterioration, and those with type 3 disease typically display a more sub acute neurological course. Type 1 Gaucher disease, the most common form accounting for more than 90% of all Gaucher disease cases, does not involve the central nervous system. The purpose of this clinical research study is to investigate the safety and effectiveness of velaglucerase alfa in patients with type 3 Gaucher disease.

Detailed Description
-----------------
Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of the enzyme glucocerebrosidase (GCB). Due to the deficiency of functional GCB, glucocerebroside accumulates within the macrophages leading to cellular engorgement, organomegaly, and organ system dysfunction. Gaucher disease has been classified into 3 clinical subtypes based on the presence or absence of neurological symptoms and severity of neurological symptoms. Patients with type 2 Gaucher disease present with acute neurological deterioration, and those with type 3 Gaucher disease typically display a more sub acute neurological course; type 1 Gaucher disease, the most common form accounting for more than 90% of all cases, does not involve the central nervous system. Velaglucerase alfa is an approved enzyme replacement therapy (ERT) for pediatric and adult patients with type 1 Gaucher disease. ERTs have been proven to reduce organomegaly, improve hematological parameters and positively impact health-related quality of life; ERTs have not been shown to cross the blood brain barrier and as a result have shown limited ability to improve the neurological (Central Nervous System; CNS) manifestations associated with Gaucher disease. This study will provide a basis for exploring the efficacy and safety of velaglucerase alfa in patients with type 3 Gaucher disease.

Official Title
-----------------
A Multi-center, Open-label, Efficacy and Safety Study of Velaglucerase Alfa Enzyme Replacement Therapy in Children and Adolescents With Type 3 Gaucher Disease

Conditions
-----------------
Gaucher Disease, Type 3

Intervention / Treatment
-----------------
* Biological: velaglucerase alfa


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Each patient must meet the following criteria to be enrolled in this study. The patient has a confirmed diagnosis of type 3 Gaucher disease. The patient is ≥ 2 and < 18 years of age at the time of enrollment. The patient is either näive to treatment or has not received treatment (investigational or approved) for Gaucher disease within 12 months prior to study entry. The patient has Gaucher disease-related anemia, defined as hemoglobin concentration below the lower limit of normal for age and sex. AND ONE OR MORE OF THE FOLLOWING THREE CRITERIA The patient has at least moderate splenomegaly (2 to 3 cm below the left costal margin) by palpation. The patient has Gaucher disease-related thrombocytopenia, defined as platelet count < 120 x 10,000 platelets/cubic mm. The patient has a Gaucher disease-related readily palpable enlarged liver. Patients who have undergone splenectomy may still be eligible to participate in the study. Female patients of child-bearing potential must agree to use a medically acceptable method of contraception at all times during the study. Pregnancy testing will be performed at the time of enrollment and as required throughout participation in the study. Male patients must agree to use a medically acceptable method of contraception at all times during the study and report a partner's pregnancy to the Investigator. The patient's parent(s) or the patient's legally authorized representative(s) has provided written informed consent that has been approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC). Exclusion Criteria: Patients who meet any of the following criteria will be excluded from this study. The patient is suspected of having type 2 or type 1 Gaucher disease. The patient is < 2 years of age. The patient has experienced a severe (Grade 3 or higher) infusion-related hypersensitivity reaction (anaphylactic or anaphylactoid reaction) to any enzyme replacement therapy for Gaucher disease (approved or investigational). The patient has received any non-Gaucher disease-related treatment with an investigational drug within 30 days prior to study entry. The patient is a pregnant and/or lactating female.

Ages Eligible for Study
-----------------
Minimum Age: 2 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: velaglucerase alfa<br>IV infusion, 60 U/kg, every other week for 1 year | Biological: velaglucerase alfa<br>* lyophilized powder, intravenous infusion, units, Every other week (EOW)<br>* Other names: Enzyme replacement therapy;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 12 Months (Week 53) in Hemoglobin Concentration | Hemoglobin concentration was measured as part of the hematology panel or measured separately when the hematology panel was not scheduled. Samples were measured by a central laboratory. Baseline is the modified baseline hemoglobin concentration, the average of the values from screening, baseline, and Week 1/Day 1. A positive change from baseline indicates that hemoglobin concentration increased. | Baseline, Week 53 or end of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 12 Months (Week 53) in Platelet Count | Platelet count was measured at a central laboratory as part of the hematology panel. Baseline is the modified baseline platelet count, the average of the values from screening, baseline and Week 1/Day 1. A positive change from baseline indicates that platelet count increased. | Baseline, Week 53 | 
| Percent Change From Baseline to 12 Months (Week 51) in Normalized Liver Volume Measured Using Magnetic Resonance Imaging (MRI) | Quantitative abdominal MRI was used to measure liver volume. If sedation was necessary to perform an MRI and the investigator deemed that this would be an unwarranted risk to the participant, liver volume could have been measured by ultrasound. Organ volume was measured by a single independent reviewer who was blinded to the participant identification and time point. The liver size relative to body weight was determined using the corresponding body weight measured at the same visit. Change in liver volume is presented as the normalized percentage of body weight. A negative change from baseline indicates that liver volume decreased. | Baseline, Week 51 or end of study | 
| Percent Change From Baseline to 12 Months (Week 51) in Normalized Spleen Volume Measured Using Magnetic Resonance Imaging (MRI) | Quantitative abdominal MRI was used to measure spleen volume. If sedation was necessary to perform an MRI and the investigator deemed that this would be an unwarranted risk to the participant, spleen volume could have been measured by ultrasound. Organ volume was measured by a single independent reviewer who was blinded to the participant identification and time point. The spleen size relative to body weight was determined using the corresponding body weight measured at the same visit. Change in spleen volume is presented as the normalized percentage of body weight. A negative change from baseline indicates that spleen volume decreased. | Baseline, Week 51 | 
| Number of Participants With Abnormal Neurological Status During The Study | Neurological symptoms were evaluated at regular intervals during the study and assessed on an individualized basis by a limited, age- and developmental stage-appropriate neurological examination adapted to suit the status of each participant. It was preferred that each neurological examination be performed by a neurologist with experience in assessment of neurological symptoms in patients with Gaucher disease and, if possible, the same neurologist (or designee) who evaluated a given participant at baseline performed the neurological examinations scheduled for that participant during the treatment phase and at the end of study visit. | Baseline, Weeks 13, 25, 37, and 53 or end of study | 
| Number of Participants Who Experienced a Treatment-Emergent Adverse Event | Adverse events (AEs) were monitored continuously throughout the study from the time the participant or participants parent/legal guardian signed the informed consent/assent (if applicable) until 30 days after the participant's last dose of study drug or at the end of study visit and/or until the event resolved or stabilized, or an outcome had been reached, whichever came first. Treatment-emergent adverse events (TEAEs) were defined as AEs which occurred on or after the time of the first infusion until 30 days after the participant's last study infusion. An infusion-related reaction is defined as an AE that 1) began either during or within 12 hours after the start of the infusion, and 2) was judged as possibly or probably related to study medication. | 57 weeks | 
| Number of Participants Who Developed Anti-Velaglucerase Alfa Antibodies During The Study | Participants provided blood samples for measurement of anti-velaglucerase alfa antibodies in serum at baseline and approximately every 12 weeks during the treatment phase. Blood samples collected during the treatment phase were to be drawn prior to infusions. Analysis of anti-velaglucerase antibodies used a validated 3-tier immunoassay method (screening, confirmatory, and titer). | Baseline, Weeks 13, 25, 37 and 53 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
VPRIV, velaglucerase alfa