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.The secondary objective of this study is to determine the long term efficacy, safety, and…
ID
Source
Brief title
Condition
- Haematological disorders NEC
- Metabolic and nutritional disorders congenital
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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.
Secondary outcome
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.
Background summary
This Phase 3 study, ENGAGE, will consist of 2 periods: The Double Blind Primary
Analysis Period (Day 1 to Week 39) and the Open Label Period (post Week 39 [Day
1 of the Open Label Period] through study completion).
The Double Blind Primary Analysis Period will include a screening period (Days
45 to 1), a dose adjustment period (Day 1 to Week 4), and a treatment period
(post Week 4 to Week 39). After the patient (and/or their parent/legal
guardian) provides informed consent, the patient will undergo Screening
assessments and, if all eligibility criteria are met, the patient will be
randomized to receive Genz 112638 or placebo for 39 weeks.
After Week 39 assessments are completed, each patient will enter the Open Label
Period where all patients will receive Genz 112638 from post Week 39 (Day 1 of
the Open Label Period) through study completion. The Open Label Period will
include a dose adjustment period (post Week 39 to Week 47), a long-term
treatment period (Week 48 through study completion which includes a safety
follow up period [30 to 37 days after the patient*s last dose of
treatment]).
In order to achieve balance between the treatment groups, all patients will be
stratified based on their spleen volume (in multiples of normal [MN]) into 1 of
2 groups. The patients within a given group will then be randomized in a 1:1
ratio to receive either Genz 112638 or placebo.
The 2 groups are as follows:
* Group 1: Low severity spleen volume (8 to 20MN)
* Group 2: High severity spleen volume (> 20 to 30MN)
DOUBLE BLIND PRIMARY ANALYSIS PERIOD:
At Screening, during the Double Blind Primary Analysis Period, patients will be
randomized (once a patient meets all of eligibility criteria) in a 1:1 ratio to
receive either Genz 112638 or placebo.
On Day 1 of the Double Blind Primary Analysis Period, patients randomized to
receive Genz 112638 will receive 50 mg of Genz 112638 (provided as one 50 mg
Genz 112638 capsule and one 100 mg placebo capsule) at the study site.
Patients randomized to receive placebo will receive matching placebo capsules
(one 50 mg placebo capsule and one 100 mg placebo capsule) at the study site.
Patients will only receive the morning dose of Genz 112638 or placebo on Day
1. The Investigator and the Genzyme Investigational Team will remain blinded
to these PK data.
BID dosing will begin on Day 2. Patients randomized to receive placebo will
receive matching placebo capsules BID (provided as one 50 mg placebo capsule
and one 100 mg placebo capsule per dose) from the morning of Day 2 until Week
39. Patients randomized to receive Genz 112638 will receive 50 mg of Genz
112638 BID (provided as one 50 mg Genz 112638 capsule and one 100 mg placebo
capsule per dose) from the morning of Day 2 until Week 4. For patients
randomized to receive Genz 112638, dose-adjustments will occur based on plasma
trough concentrations of Genz 99067 collected during the Week 2 PK. For
patients who have a Genz 99067 plasma trough concentration of < 5 ng/mL, the
treatment dose will be increased at Week 4 to 100 mg of Genz 112638 BID
(provided as one 100 mg Genz 112638 capsule and one 50 mg placebo capsule per
dose) for the remainder of the Double Blind Primary Analysis Period. Patients
who have a Genz 99067 plasma trough concentration of * 5 ng/mL will continue to
receive 50 mg of Genz 112638 BID (provided as one 50 mg Genz 112638 capsule and
one 100 mg placebo capsule per dose) for the remainder of the Double Blind
Primary Analysis Period.
During the Double Blind Primary Analysis Period, the patient, Investigator, and
the Genzyme Investigational Team will be blinded to the identity of the placebo
or Genz 112638 capsules; the Investigator and the Genzyme Investigational Team
will also be blinded to the PK data. Genzyme Clinical Pharmacy Research
Services will remain unblinded throughout the study in order to provide the
appropriate investigational product to patients. The appropriate drug kits
will be assigned to each patient by Interactive Voice Response
System/Interactive Web Response System (IVRS/IWRS) according to treatment
randomization and dose adjustment PK results provided by the Central
Laboratory. Note: The Primary Analysis Period will not be unblinded until all
patients have completed the Double Blind Primary Analysis Period.
OPEN LABEL PERIOD:
After all Week 39 study assessments have been completed, patients will enter
the Open Label Period. On Day 1 of the Open Label Period, all patients will
begin BID dosing and will receive their morning dose of 50 mg of Genz 112638
(provided as one 50 mg Genz 112638 capsule) at the study site to allow for
blood sample collection at the scheduled post-dose time points for 4-hour PK
analysis. All patients will receive 50 mg of Genz 112638 BID (provided as one
50 mg Genz 112638 capsule per dose) until Week 43.
Dose-adjustments during the Open-Label Period will occur based on plasma trough
concentrations of Genz 99067 collected during the Week 41and Week 45 PK. For
patients who have a Genz 99067 plasma trough concentration of < 5 ng/mL at Week
41, the treatment dose will be increased at Week 43 to 100 mg of Genz 112638
BID (provided as one 100 mg Genz 112638 capsule per dose). Patients who have a
Genz 99067 plasma trough concentration of * 5 ng/mL at Week 41 will continue to
receive 50 mg of Genz 112638 BID (provided as one 50 mg Genz 112638 capsule per
dose) until Week 47. Plasma trough concentrations of Genz 99067 will be
collected for all patients during Week 45. For patients who have a Genz 99067
plasma trough concentration of <5 ng/mL at Week 45, the Genz 112638 dose will
be increased at Week 47 either from 50 mg to 100 mg of Genz 112638 BID or from
100 mg to 150 mg of Genz 112638 BID for the remainder of the Open-Label
Period. Patients receiving 50 mg or 100 mg of Genz 112638 who have a Genz
99067 plasma trough concentration of *5 ng/mL at Week 45 will continue to
receive 50 mg or 100 mg of Genz 112638 BID for the remainder of the Open-Label
Period. During the Open Label Period, patients will return to the study site
at Weeks 41, 43, 45, 47, and 52, and every 3 months thereafter until study
completion.
Study objective
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.
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.
Study design
See 'Background of the study'.
Intervention
See 'Background of the study'.
Study burden and risks
The burden for the patients is as follows:
- A significant time investment is required. 18 visits are planned in the first
130 weeks. After which the patients will be required to visit the site every 3
months. On average, each visit wil take 1 to 8 hours.
- Some invasive assessments are scheduled:
1. PK assessments at most visits until Week 130 and annually thereafter. See
protocol table 9-4 in section 9.5 (Pharmacokinetic Assessments).
2. In this study, an X-ray will be done of the chest and spine. The energy of
the light used for the photographs may cause cell damage. This damage is mostly
repaired by the body. The radiation committee qualifies the risk of the
effective dose as intermediate.
Gooimeer 10
1411DD Naarden
NL
Gooimeer 10
1411DD Naarden
NL
Listed location countries
Age
Inclusion criteria
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 * 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 100,000/mm3 (the mean of 2 measurements from separate blood samples collected at least 24 hours apart during Screening).
B. Splenomegaly (spleen volume of 8 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 or grapefruit juice for 72 hours prior to administration of the first dose of study medication and throughout the duration of the Double-Blind Primary Analysis Period.
Exclusion criteria
1. The patient has had a partial or total splenectomy.
2. The patient has received pharmacological chaperone or 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 documentation of acute pathological bone involvement (e.g. osteonecrosis and/or pathological fractures, as assessed by X ray and/or magnetic resonance imaging [MRI]) as determined in review with a central bone reviewer or has 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 >100,000/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, in the opinion of the Investigator, 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 CYP3A4 or CYP2D6 inducer within 30 days prior to randomization.
21. 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, 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 and has received (acute or chronic) treatment with a strong inhibitor of CYP3A4 within 30 days prior to randomization.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-005222-37-NL |
| ClinicalTrials.gov | NCT00891202 |
| CCMO | NL28189.018.09 |