Intra-monocyte Imiglucerase Kinetics in Gaucher Disease (CIMI)

• ClinicalTrials.gov Identifier: NCT01951989
• Recruitment Status: Unknown
• First Posted: September 27, 2013
• Last Update Posted: September 27, 2013
• Sponsor: University Hospital, Clermont-Ferrand
• Information provided by (Responsible Party): University Hospital, Clermont-Ferrand

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Gaucher Disease	Drug: Imiglucérase (drug) pharmacokinetics	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Study of Intra-monocytic Imiglucerase Kinetic and Its Correlation With Clinical and Biological Gaucher Disease
• Study Start Date: November 2012
• Estimated Primary Completion Date: February 2016
• Estimated Study Completion Date: June 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Enzyme intra-monocyte activity (sum of endogenous enzyme activities and therapeutic enzyme)in patients treated with imiglucerase [ Time Frame: at day 1 ]
   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.

Secondary Outcome Measures :

1. Residual rate [ Time Frame: every 6 months during 2 years. ]
   Pharmacokinetics descriptive criteria are the area under curve at balance, the terminal half-life and the residual rate.
2. Endogeneous intra-monocyte glucocérébrosidase activity from untreated patients [ Time Frame: every 6 months during 2 years ]
3. Biomarker dosages will provide serum concentration values [ Time Frame: at D0, M3, M6 and every 6 months during 2 years: ]

   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

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Contacts

Contact: Patrick LACARIN; 04 73 75 11 95; placarin@chu-clermontferrand.fr

Locations

France

CHU Clermont-Ferrand; Recruiting

Clermont-Ferrand, France, 63003

Contact: Patrick LACARIN 04 73 75 11 95 placarin@chu-clermontferrand.fr

Principal Investigator: Marc BERGER

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

Sponsors and Collaborators

University Hospital, Clermont-Ferrand

Investigators

• Principal Investigator: Marc BERGER; University Hospital, Clermont-Ferrand

More Information

• Responsible Party: University Hospital, Clermont-Ferrand
• ClinicalTrials.gov Identifier: NCT01951989
• Other Study ID Numbers: CHU-0167; 2012-019622-13
• First Posted: September 27, 2013
• Last Update Posted: September 27, 2013
• Last Verified: September 2013

Keywords provided by University Hospital, Clermont-Ferrand:

Gaucher disease; Imiglucerase; Pharmacokinetics

Additional relevant MeSH terms:

Gaucher Disease; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders