Clinical Trials Register

Summary
EudraCT Number:	2008-005223-28
Sponsor's Protocol Code Number:	GZGD02607
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2009-07-01
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2008-005223-28

A.3

Full title of the trial

A Phase 3, Randomized, Multi-Center, Multi-National, Open-Label, Active Comparator Study to Evaluate the Efficacy and Safety of Genz-112638 in Patients with Gaucher Disease Type 1 who have Reached Therapeutic Goals with Enzyme Replacement Therapy

A.3.2

Name or abbreviated title of the trial where available

ENCORE

A.4.1

Sponsor's protocol code number

GZGD02607

A.7

Trial is part of a Paediatric Investigation Plan

Information not present in EudraCT

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Genzyme Europe B.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/07/514
D.3 Description of the IMP
D.3.1	Product name	Genz-112638
D.3.2	Product code	Genz-112638
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Eliglustat
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	Genz-112638
D.3.9.3	Other descriptive name	not available
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Cerezyme
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe B.V.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Cerezyme
D.3.2	Product code	Imiglucerase
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Information not present in EudraCT
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IMIGLUCERASE
D.3.9.1	CAS number	154248-97-2
D.3.9.3	Other descriptive name	Recombinant human derived macrophage-targeted β-Glucocerebrosidase
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	60
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Information not present in EudraCT
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	Information not present in EudraCT
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Information not present in EudraCT
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	Yes
D.3.11.13.1	Other medicinal product type	Recombinant human derived macrophage-targeted ß-glucocerebrosidase

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Gaucher Disease type I

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	9.1
E.1.2	Level	PT
E.1.2	Classification code	10018048
E.1.2	Term	Gaucher's disease

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 therapy (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

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. Within the 9 months prior to randomization, the patient has received a total monthly dose of 30 to 130 U/kg for at least 6 months.
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, and no documentation of acute pathological bone involvement by imaging (e.g., osteonecrosis, pathological fractures, etc.) as determined in review with a
central bone reviewer.
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 or grapefruit juice 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 pharmacological chaperone, taliglucerase, or 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 a documented deficiency of iron, vitamin B-12, or folate that requires treatment not yet initiated or not yet stable under treatment for at least 3 months prior to randomization.
6. 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.
7. 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, in the opinion of the
Investigator, may preclude participation in the study.
8. 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).
9. The patient has tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen.
10. The patient has received an investigational product within 30 days prior to randomization.
11. The patient is scheduled for in-patient hospitalization, including elective surgery, during the study.
12. The patient has a history of cancer within 5 years of randomization, with the exception of basal cell carcinoma.
13. The patient is pregnant or lactating.
14. The patient has received any medication that may cause QTc interval prolongation within 30 days prior to randomization.
15. The patient has received any medication that may induce CYP2D6 or 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.
16. The patient is not a CYP2D6 poor metabolizer, 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.
17. The patient is a CYP2D6 poor metabolizer 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.
18. 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.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

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

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

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

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

Information not present in EudraCT

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

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

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.3

Elderly (>=65 years)

Yes

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

186

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

After trial completion, or in the event the trial should be halted, the treating physician will discuss with the patient the available alternative treatments after study completion.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2009-07-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2009-11-04

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-02

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