Intra-monocyte Imiglucerase Kinetics in Gaucher Disease (CIMI)

Study of Intra-monocytic Imiglucerase Kinetic and Its Correlation With Clinical and Biological Gaucher Disease

Rational: Imiglucerase has been used to treat Gaucher disease since 1997 but data about its pharmacokinetics have been partial; investigators know that imiglucerase undergoes a quick clearance from plasma compartment following the infusion (1/2 life: 1-6 min, from tissue: <24h), an observation apparently contradictory with usual infusion rhythm (one infusion every two weeks). Furthermore, by going by GD response, the rhythm of Infusion is sometimes diminished (for example, every 3 or 4 wks) without pharmacological rational ; In parallel, investigators demonstrated that monocytes represent a satisfactory surrogate of GD target cells and that enzyme activity into monocytes varies between individuals.

Our hypothesis is that enzyme activity into monocyte compartment could be different and could be related to GD response.

Primary purpose: to evaluate the pharmacokinetics of Imiglucerase activity into target cellular compartment depending on dose and frequency of infusions.

Secondary purposes : 1) to establish a possible relationship between the intra-monocytic activity of glucocerebrosidase and the clinical and biological activity of Gaucher disease and to define a possible threshold value of enzyme activity; 2) to establish a better correlation with known biomarkers of disease (routine markers and markers recently identified), which would better predict and / or monitor response to treatment ; 3) to compare the residual and natural rate of activity enzyme intra-monocytic for untreated patients (low severity disease).

Study Overview

• Status: Unknown
• Conditions: Gaucher Disease
• Intervention / Treatment: Drug: Imiglucérase (drug) pharmacokinetics

Detailed Description

Rational: Imiglucerase has been used to treat Gaucher disease since 1997 but data about its pharmacokinetics have been partial; investigators know that imiglucerase undergoes a quick clearance from plasma compartment following the infusion (1/2 life: 1-6 min, from tissue: <24h), an observation apparently contradictory with usual infusion rhythm (one infusion every two weeks). Furthermore, by going by GD response, the rhythm of Infusion is sometimes diminished (for example, every 3 or 4 wks) without pharmacological rational ; In parallel, investigators demonstrated that monocytes represent a satisfactory surrogate of GD target cells and that enzyme activity into monocytes varies between individuals. Our hypothesis is that enzyme activity into monocyte compartment could be different and could be related to GD response.

Primary purpose: to evaluate the pharmacokinetics of Imiglucerase activity into target cellular compartment depending on dose and frequency of infusions.

Secondary purposes : 1) to establish a possible relationship between the intra-monocytic activity of glucocerebrosidase and the clinical and biological activity of Gaucher disease and to define a possible threshold value of enzyme activity; 2) to establish a better correlation with known biomarkers of disease (routine markers and markers recently identified), which would better predict and / or monitor response to treatment ; 3) to compare the residual and natural rate of activity enzyme intra-monocytic for untreated patients (low severity disease).

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • Recruiting
    • Chu Clermont-Ferrand
    • Sub-Investigator: Nadia BELMATOUG
    • Sub-Investigator: Agathe MASSEAU
    • Sub-Investigator: Christine SERRATRICE
    • Sub-Investigator: Christian ROSE
    • Sub-Investigator: Vassili VALAYANNOPOULOS
    • Sub-Investigator: Thierry BILLETTE DE VILLEMEUR
    • Sub-Investigator: Olivier LIDOVE
    • Sub-Investigator: Christian LAVIGNE
    • Sub-Investigator: Pierre KAMINSKY
    • Sub-Investigator: Yves-Marie PERS
    • Sub-Investigator: Catherine CAILLAUD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient older than 12 years old with Gaucher disease type 1 or type 3 and having signed an informed consent
• Treated with imiglucerase (Cerezyme ®) with a stable therapeutic strategy for at least 3 months.

OR

• Untreated patient, with no therapeutic indication at the time of inclusion and having a diagnosis older than 2 years (non progressive disease)
• Patients must have a social security system

Exclusion Criteria:

• Age <12 years old
• Gaucher disease unproven
• Gaucher disease treated with therapeutic changes in the previous 3 months, or current treatment different from imiglucerase
• Gaucher disease untreated whose diagnosis was established for under 2 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Imiglucerase; Primary purpose: to evaluate the pharmacokinetics of Imiglucerase activity into target cellular compartment depending on dose and frequency of infusions. Secondary purposes : 1) to establish a possible relationship between the intra-monocytic activity of glucocerebrosidase and the clinical and biological activity of Gaucher disease and to define a possible threshold value of enzyme activity; 2) to establish a better correlation with known biomarkers of disease (routine markers and markers recently identified), which would better predict and / or monitor response to treatment ; 3) to compare the residual and natural rate of activity enzyme intra-monocytic for untreated patients (low severity disease).

Drug: Imiglucérase (drug) pharmacokinetics

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Enzyme intra-monocyte activity (sum of endogenous enzyme activities and therapeutic enzyme)in patients treated with imiglucerase	Enzyme intra-monocyte activity (sum of endogenous enzyme activities and therapeutic enzyme) in patients treated with imiglucerase will be assessed at different times between infusions (8 to 10 time points), and just before an infusion (residual rate). The population pharmacokinetics method allows to perform this analysis in measurement windows that are not necessarily included in the period between two consecutive infusions of imiglucerase but may be spread over several cycles.	at day 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Residual rate	Pharmacokinetics descriptive criteria are the area under curve at balance, the terminal half-life and the residual rate.	every 6 months during 2 years.
Endogeneous intra-monocyte glucocérébrosidase activity from untreated patients		every 6 months during 2 years
Biomarker dosages will provide serum concentration values	1) routine biomarkers (ACE, TRAP, chitotriosidase, ferritin) and 2) potentially interesting biomarkers but not routinely evaluated in France (CCL18, MIP1a, MIP1b, MCP1, IL-8, glycated ferritin). - Gaucher disease status will be assessed by clinical and biological criteria defined by the HAS (Haute Autorité de Santé = High Health Authority). We will consider the two-year periods before and after treatment to identify progressive diseases (clinical or biological significant events associated with Gaucher disease in the two years before and 2 years after the enrolment time	at D0, M3, M6 and every 6 months during 2 years:

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (ANTICIPATED): February 1, 2016
• Study Completion (ANTICIPATED): June 1, 2016

Study Registration Dates

• First Submitted: September 2, 2013
• First Submitted That Met QC Criteria: September 24, 2013
• First Posted (ESTIMATE): September 27, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): September 27, 2013
• Last Update Submitted That Met QC Criteria: September 24, 2013
• Last Verified: September 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Gaucher disease; Imiglucerase
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gaucher Disease
• Other Study ID Numbers: CHU-0167; 2012-019622-13