| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| People with Gaucher disease have low levels of an enzyme called acid ß-glusosidase which helps the body controls levels of glucosylceramide. In Gaucher disease glucosylceramide levels can get too high |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10018048 |
| E.1.2 | Term | Gaucher's disease |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to assess the efficacy and safety of Genz-112638 compared with Cerezyme after 52 weeks of treatment in patients with Gaucher disease type 1 who have reached therapeutic goals with enzyme replacement therpay (ERT) |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to demonstrate that, in patients with Gaucher disease type 1 who have reached therapeutic goals with ERT, the majority of patients who receive Genz-112638 remain stable after 52 weeks of treatment. The tertiary objective of this study is to evaluate the long-term efficacy, safety, and pharmacokinetics (PK) of Genz-112638 in patients with Gaucher disease type 1 who have reached therapeutic goals with ERT. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria in order to
participate in this study:
1.The patient is willing and able to provide signed informed consent
prior to any protocol-required procedures to be performed.
2.The patient is at least 18 years of age at the time of randomization.
3.The patient's Tanner Stage should be ≥ 4 prior to randomization.
4.The patient has a diagnosis of Gaucher disease type 1 confirmed by a documented deficiency of acid β-glucosidase activity by enzyme assay.
5.The patient consents to provide a blood sample for genotyping for
Gaucher disease, chitotriosidase, and cytochrome P450 2D6 (CYP2D6, to categorize the patient's predicted rate of metabolism), if these genotyping results are not already available for the patient.
6.The patient has received treatment with ERT for at least 3 years. For at least 6 of the 9 months prior to randomization, the patient has received a total monthly dose of 30 to 130 U/kg of ERT that has received approval by at least one regulatory authority by the time of randomization.
7.The patient has reached Gaucher disease therapeutic goals prior to randomization. Gaucher disease therapeutic goals are defined as a patient with all of the following:
A.No bone crisis and free of symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathological fractures within the last year.
B.Mean hemoglobin level of ≥ 11 g/dL if female and ≥ 12 g/dL if male at the time of screening.
C.Mean platelet count ≥ 100,000/mm3 at the time of screening.
8.Spleen volume < 10 times Normal or total splenectomy (provided the splenectomy occurred > 3 years prior to randomization).
9.Liver volume < 1.5 times Normal.
10.Female patients of childbearing potential must have a documented negative pregnancy test prior to randomization. In addition, all female patients of childbearing potential must use a medically accepted form of contraception throughout the study (either a barrier method or hormonal contraceptive with ethinyl estradiol and norethindrone or similar active components).
11.The patient is willing to abstain from consumption of grapefruit,
grapefruit juice, or grapefruit products for 72 hours prior to
administration of the first dose of study medication (Genz 112638 or Cerezyme) and, if randomized to Genz 112638, for the duration of the primary analysis period. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from participation in this study if they meet
any of the following exclusion criteria:
1.The patient received substrate reduction therapies for Gaucher disease within 6 months prior to randomization.
2.The patient has had a partial or total splenectomy within 3 years prior to randomization.
3.The patient has any evidence of neurologic (e.g., peripheral
neuropathy, tremor, seizures, Parkinsonism or cognitive impairment) or pulmonary involvement (e.g., pulmonary hypertension) as related to Gaucher disease.
4.The patient is transfusion-dependent.
5.The patient has documented prior esophageal varices or liver
infarction or current liver enzymes (alanine transaminase
[ALT]/aspartate aminotransferase [AST]) or Total Bilirubin > 2 times the upper limit of normal (ULN), unless the patient has a diagnosis of Gilbert Syndrome.
6.The patient has any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (e.g. hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may preclude participation in the study.
7.The patient is known to have any of the following: Clinically significant coronary artery disease including history of myocardial infarction (MI) or ongoing signs or symptoms consistent with cardiac ischemia or heart failure; or clinically significant arrhythmias or conduction defect such as 2nd or 3rd degree atrioventricular (AV) block, complete bundle branch block, prolonged QTc interval, or sustained ventricular tachycardia (VT).
8.The patient has tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen.
9.The patient has received an investigational product within 30 days
prior to randomization.
10.The patient is scheduled for in-patient hospitalization, including
elective surgery, during the study.
11.The patient has a history of cancer within 5 years of randomization, with the exception of basal cell carcinoma.
12.The patient is pregnant or lactating.
13.The patient has received any medication that may cause QTc interval prolongation within 30 days prior to randomization. Exception:
Diphenhydramine (Benadryl) or other medications used as
premedication for ERT infusions are allowed up to 7 days prior to randomization.
14.The patient has received any medication that may induce CYP3A4
within 30 days prior to randomization, with the exception of
premedications for ERT infusion, which are allowed up to 7 days prior to randomization.
15.The patient is not a CYP2D6 poor metabolizer, or is an indeterminate metabolizer with one allele identified as active, and has received any medication that is a strong inhibitor of CYP3A4 or CYP2D6 within 30 days prior to randomization, with the exception of the following:
•premedications for ERT infusion, which are allowed up to 7 days prior to randomization;
•a strong inhibitor of CYP3A4 or a strong inhibitor of CYP2D6 (but not both medications) that has been administered chronically for at least 30 days prior to randomization and will be continued on the same dosing regimen during the primary analysis period.
16.The patient is a CYP2D6 poor metabolizer or an indeterminate
metabolizer with neither allele known to be active and has received any medication that is a strong inhibitor of CYP3A4 within 30 days prior to randomization, with the exception of premedications for ERT infusion, which are allowed up to 7 days prior to randomization.
17.The patient is unable to receive treatment with Cerezyme due to a known hypersensitivity or is unwilling to receive Cerezyme treatment q2w. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint will be the percentage (%) of patients who remain stable for 52 weeks (the primary analysis period) assessed for both treatment groups separately along with a difference between the two treatment groups. For a patient to be considered to have demonstrated a clinically meaningful response to treatment with Genz-112638 or Cerezyme, patients must remain stable in hematological parameters (hemoglobin levels and platelet counts), and organ volumes (spleen, when applicable, and liver volumes in multiples of normal [MN]). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| The secondary efficacy endpoints will include the following: Total T- and Z-scores for bone mineral density (dual-energy X-ray absorptiometry [DXA]) of femur and lumbar spine, hemoglobin level, platelet count, and spleen and liver volumes (in MN) (assessed by magnetic resonance imaging [MRI]). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Czech Republic |
| Egypt |
| France |
| Germany |
| Italy |
| Netherlands |
| Russian Federation |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last patient last visit plus a safety follow-up period (30 to 37 days after the patient's last dose of treatment) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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