| 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-glucosidase, which helps the body control levels of glucosylceramide. In Gaucher Disease glucosylceramide levels can get too high |
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| 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 | 14.1 |
| 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 |
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| 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 confirm the efficacy and safety of Genz 112638 after 39 weeks of treatment in patients with Gaucher disease type 1. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to determine the long-term efficacy, safety, and pharmacokinetics (PK) of Genz 112638 in patients with Gaucher disease type 1. |
|
| 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 (and/or their parent/legal guardian) is willing and able to provide signed informed consent prior to any study-related procedures to be performed.
2. The patient is at least 16 years old 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 has the following symptoms of Gaucher disease during the Screening period:
A. At least one of the following laboratory abnormalities:
1. Hemoglobin level of 8.0 to 11.0 g/dL if female or 8.0 to 12.0 g/dL if male (the mean of 2 measurements from separate blood samples collected at least 24 hours apart during Screening).
2. Platelet count of 50,000 to 130,000/mm3 (the mean of 2 measurements from separate blood samples collected at least 24 hours apart during Screening).
B. Splenomegaly (spleen volume of 6 to 30MN).
C. If hepatomegaly is present, the liver volume must be < 2.5MN.
6. The patient consents to provide a blood sample to Genzyme for genotyping for Gaucher disease, chitotriosidase, and cytochrome P450 2D6 (CYP2D6, to categorize the patient’s predicted rate of metabolism), unless the patient’s genotypes for Gaucher disease, chitotriosidase, and CYP2D6 are already available.
7. 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).
8. 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 and throughout the duration of the Double-Blind 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 has had a partial or total splenectomy.
2.The patient has received substrate reduction therapies for Gaucher disease within 6 months prior to randomization.
3.The patient has received enzyme replacement therapy for Gaucher disease within 9 months prior to randomization.
4.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.
5.The patient has current symptomatic bone disease such as bone pain attributable to osteonecrosis and/or pathologic fracture, or has had a bone crisis in the 12 months prior to randomization.
6.The patient is transfusion dependent.
7.The patient has the following laboratory abnormalities during the Screening period:
A.Hemoglobin level < 8 g/dL (the mean of 2 measurements from separate blood samples collected at least 24 hours apart during Screening).
B.Platelet count of < 50,000/mm3 (the mean of 2 measurements from separate blood samples collected at least 24 hours apart during Screening).
8.The patient has documented anemia due to causes other than Gaucher disease that requires treatment not yet initiated or not yet stable under treatment for at least 3 months (e.g., iron, vitamin B-12, and/or folate deficiency) prior to randomization.
9.The patient has documented thalassemia minor or sickle cell trait with a platelet count of < 50,000 or >130,000/mm3.
10.The patient has ever had any radiation treatment in the abdominal region.
11.The patient has documented prior esophageal varices or liver infarction or current liver enzymes (alanine aminotransferase [ALT]/ aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal (ULN), unless the patient has a diagnosis of Gilbert Syndrome.
12.The patient has any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), 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.
13.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).
14.The patient has tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen.
15.The patient has received an investigational product within 30 days prior to randomization.
16.The patient is scheduled for in patient hospitalization, including elective surgery, during the study.
17.The patient has a history of cancer within 5 years of randomization, with the exception of basal cell carcinoma.
18.The patient is pregnant or lactating.
19.The patient has received any medication that may cause QTc interval prolongation within 30 days prior to randomization
20.The patient has received (acute or chronic) treatment with a cytochrome P450 3A4 (CYP3A4) inducer within 30 days prior to randomization.
21.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, except where a patient has been receiving chronic treatment with either a strong inhibitor of CYP3A4 or a strong inhibitor of CYP2D6 (but not both medications) for at least 30 days prior to randomization and plans to continue on the same dosing regimen during the Double-Blind Primary Analysis Period.
22.The patient is a CYP2D6 poor metabolizer or an indeterminate metabolizer with neither allele known to be active and has received (acute or chronic) treatment with a strong inhibitor of CYP3A4 within 30 days prior to randomization.
|
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the percentage change in spleen volume (in MN) from Baseline to 39 weeks of treatment with Genz 112638 as compared to placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Secondary efficacy endpoints include the following: Absolute changes from Baseline in hemoglobin level (in g/dL), percentage changes from Baseline in liver volume (in MN), and percentage changes from Baseline in platelet count. An additional secondary analysis for patients treated with Genz-112638 will include analyses of within-patient change from Baseline to 39 Weeks for the following: percentage change in spleen volume (MN); absolute change in hemoglobin level (in g/dL), percentage change in liver volume (in MN), and percentage change in platelet count. |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
| Bulgaria |
| Canada |
| Colombia |
| India |
| Israel |
| Jordan |
| Lebanon |
| Mexico |
| Netherlands |
| Russian Federation |
| Saudi Arabia |
| Serbia |
| Tunisia |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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