The primary objectives of this study are: * To characterize the effects of 150 mg and 450 mg of AT1001 administered 2 hours before administration of agalsidase on the safety and plasma pharmacokinetics of agalsidase in subjects with Fabry Disease*…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoints:
* AT1001 plasma pharmacokinetic parameter values after administration of a
single oral dose of AT1001 alone and in combination with agalsidase
* Agalsidase plasma pharmacokinetic parameter values by measurement of *-Gal A
enzyme levels and protein levels after agalsidase infusion alone and in
combination with AT1001
* Safety variables: adverse events, clinical laboratory tests, 12-Lead ECGs,
physical examinations, vital signs and infusion reactions
Secondary outcome
Secondary Endpoint:
* Distribution of agalsidase to skin after dosing with agalsidase alone and
agalsidase in combination with AT1001 at 24 hours and 7 days after dosing by
measuring *-Gal A levels and protein levels
Exploratory Endpoints:
* Urinary GL-3 excretion before and 14 days after each agalsidase dose
* GL-3 in skin after dosing with agalsidase alone and agalsidase in combination
with AT1001 at 24 hours and 7 days after dosing
* WBC *-Gal A enzyme levels, determined before initiation of the agalsidase
infusion and at 2, 4 and 24 hours and 7 and 14 days after dosing
* Antibody titer (IgG) before initiation of an infusion of agalsidase
* Plasma globotriaosylsphingosine (lyso-GB3) concentrations and urinary
excretion of lyso-GB3 before each dose of agalsidase and 14 days after each
dose of agalsidase
Background summary
This study will provide drug-drug interaction information after
co-administration of AT1001 and agalsidase to support dosing instructions for
AT1001. In addition, information on the effect of 150 mg and 450 mg doses of
AT1001 on agalsidase will be obtained for proof of concept that AT1001 has the
potential to improve the pharmacokinetic properties of agalsidase. Patients
receiving either agalsidase alfa (Replagal*) or agalsidase beta (Fabrazyme®)
will be eligible to participate in this study. A favorable change in the
disposition of agalsidase may support further development of AT1001 in
combination with Enzyme Replacement Therapy.
Study objective
The primary objectives of this study are:
* To characterize the effects of 150 mg and 450 mg of AT1001 administered 2
hours before administration of agalsidase on the safety and plasma
pharmacokinetics of agalsidase in subjects with Fabry Disease
* To characterize the effect of agalsidase on the safety and plasma
pharmacokinetics of 150 mg of AT1001 administered 2 hours before administration
of agalsidase in subjects with Fabry Disease
The secondary objective of this study is:
* To characterize the effect of 150 mg and 450 mg AT1001 on the distribution of
*-Gal A to skin after administration of agalsidase
Study design
This open-label study will consist of two stages. Stage 1 will consist of
screening and a three period study to evaluate the effect of 150 mg AT1001 on
the pharmacokinetics and safety of agalsidase and the effect of agalsidase on
the pharmacokinetics and safety of 150 mg AT1001. Stage 2 will consist of
screening and a two-period study to evaluate the effect of 450 mg AT1001 on the
pharmacokinetics and safety of agalsidase. In Stage 2, the effect of
agalsidase on the pharmacokinetics and safety of a 450 mg dose of AT1001 will
not be evaluated; the plasma exposure of AT1001 will be characterized when
AT1001 is administered with agalsidase solely to confirm the attainment of
adequate AT1001 plasma concentrations.
Intervention
Stage 1
Each subject will receive each of the following treatments in the order
described below:
Period 1: Agalsidase alone as an intravenous infusion
Period 2: A 150 mg oral dose of AT1001 two hours before initiation of an
intravenous infusion of agalsidase
Period 3: A 150 mg oral dose of AT1001
Note: the dose of agalsidase administered in Periods 1 and 2 will be
identical. Agalsidase alfa will be administered as a 40-minute intravenous
infusion; agalsidase beta will be administered as a 2 hour intravenous infusion.
Stage 2
Each subject will receive each of the following treatments in the order
described below:
Period 1: Agalsidase alone as an infusion
Period 2: A 450 mg oral dose of AT1001 two hours before initiation of an
intravenous infusion of agalsidase
Note: the dose of agalsidase administered in Periods 1 and 2 will be identical.
Agalsidase alfa will be administered as a 40-minute intravenous infusion;
agalsidase beta will be administered as a 2 hour intravenous infusion.
Study burden and risks
Non-clinical studies have shown that AT1001 has the potential to improve the
efficacy of enzyme replacement therapy in patients with Fabry disease. It is
not known if the improvement in enzyme efficacy observed in vitro and in mice
and rats will also be demonstrated in humans. The objective of this study is
to provide data to support potential clinical studies evaluating the efficacy
of AT1001 in combination with enzyme replacement therapy with Fabrazyme and
Replagal in patients with Fabry.
6 Cedar Brook Drive
Cranbury, NJ 08512
US
6 Cedar Brook Drive
Cranbury, NJ 08512
US
Listed location countries
Age
Inclusion criteria
1. Male, diagnosed with Fabry disease and between 18 and 65 years of age, inclusive
2. Body Mass Index (BMI) between 18-35
3. Subject initiated treatment with agalsidase at least 1 month, having received at least two infusions, before Screening Visit
4. Subject*s dose level, dosing regimen and form (i.e., alfa or beta) of agalsidase have been stable (stable dose defined as not varying by more than ± 20%) for at least 1 month before Screening Visit
5. Subject has a estimated creatinine clearance * 60 mL/min at Screening; creatinine clearance to be estimated using the 4-parameter MDRD equation:
eGFR (mL/min/1.73 m2) <= 186 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African-American)
6. Subject agrees to use medically accepted methods of contraception during the study and for 30 days after study completion
7. Subject is willing and able to provide written informed consent
Exclusion criteria
1. Subject has had a documented transient ischemic attack, ischemic stroke, unstable angina, or myocardial infarction within the 3 months before Screening
2. Subject has clinically significant unstable cardiac disease (e.g., cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or NYHA class III or IV congestive heart failure)
3. Subject has a history of allergy or sensitivity to study drug (including excipients) or other iminosugars (e.g., miglustat, miglitol)
4. Subject requires a concomitant medication prohibited by the protocol: Glyset® (miglitol), or Zavesca® (miglustat)
5. Any investigational/experimental drug or device within 30 days of Screening
6. Subject is currently being treated with or has previously received AT1001
7. Subject has any intercurrent illness or condition that may preclude the subject from fulfilling the protocol requirements or suggests to the investigator that the potential subject may have an unacceptable risk by participating in this study
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 | EUCTR2010-022709-16-NL |
| ClinicalTrials.gov | NCT01196871 |
| CCMO | NL34807.018.10 |