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LYSO-PROVE - Determine the Prognostic Value of Lyso-Gb1 for Monitoring the Progress of Gaucher Disease (LYSO-PROVE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02416661
Recruitment Status : Recruiting
First Posted : April 15, 2015
Last Update Posted : April 30, 2019
Information provided by (Responsible Party):
Centogene AG Rostock

Brief Summary:
This study should demonstrate the correlation and predictive value of lyso-Gb1 concentration with the clinical severity of naïve, initially non-ERT/SRT Gaucher disease type 1 and during the study ERT/SRT-newly started Gaucher type 1 patients

Condition or disease
Lysosomal Storage Diseases Gaucher Disease Sphingolipidoses

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Detailed Description:

Gaucher disease is an autosomal recessive inherited lysosomal storage disorder. The disease is caused by the hereditary deficiency of the glucocerebrosidase, a lysosomal enzyme that breaks down glucocerebroside into glucose and ceramide. Gaucher disease is the most common sphingolipidosis and it is among the most frequent inherited diseases among the ethnic group of Ashkenazi Jews. The gene that encodes for glucocerebrosidase is located on the long arm of the chromosome 1 and contains 11 exons. So far, more than 400 different mutations have been described in Gaucher patients, the most frequent of which is the missense mutation but also the frame-shift and splice-site mutation and insertions and deletions are known. The more frequent mutations are N370S, L444P, IVS2+1G>A, c.84insG, R463C, and R496H. Clinical symptoms are numerous. The classical symptoms affect visceral organs (hepatosplenomegaly) and the skeletal system (bone marrow infiltrations up to bone infarcts and pathological fractures) with consecutive changes in the blood panel (anemia, thrombocytopenia) (Sidransky, 2004).A major distinguishing factor is the occurrence of neurological manifestations (myoclonus epilepsy, hydrocephalus, eye motion disorders). Today, it is discussed whether the division into the classical three types of disease (type 1: non-neuronopathic form; type 2: the acute neuronopathic form; type 3: the chronic neuronopathic form) are still applicable because in clinical practice the presenting symptoms are only insufficiently reflected with this classification.

There is no clear genotype-phenotype relationship. The same DNA mutation is seen in patients with a completely different characterization of the disease. An exception is the mutation N370S, which so far has been found only in the visceral form (type1), but still may have a high phenotypic heterogeneity in GD Type 1 (Fairley et al., 2008).

The outcome of the non-neuronopathic diseases could be improved greatly with the introduction and widely available enzyme replacement therapy. Among these are the reductions of the size of the liver and spleen as well as normalization in the blood count (Elstein and Zimran, 2009). The glucocerebrosides that are not metabolized are stored in the entire reticuloendothelial system. The macrophages enriched with glycolipids form the pathoanatomic basis of the so-called "Gaucher cells" which can be verified with the light microscope. The accumulation of Gaucher cells in liver, spleen, and bone marrow is thought to underlie the characteristic hepatosplenomegaly, pancytopenia and bone complications of GD patients (Beutler 2001). There are no causative cures for lysosomal storage diseases and treatment is mostly symptomatic, although mostly enzyme replacement therapy (ERT) has been demonstrated especially for the treatment of non-neuronopathic GD with good success (Elstein and Zimran, 2009). In addition, substrate reduction therapy (SRT), a method used to decrease the accumulation of storage material, is currently being evaluated for some of these diseases. In SRT, oral administration of the iminosugar N-butyldeoxynojirimycin aims to reduce Glucosylceramide (GlcCer) synthesis and thus limit its accumulation. However, SRT is only approved for mildly tomoderately affected patients in whom ERT is not a therapeutic option (Ficicioglu, 2008). Additionally, Eliglustat is currently under investigation for the primary oral treatment of GD type 1 patient (Lukina et al., 2014).

To date a definitive diagnosis of Gaucher's disease can only be made applying biochemical testing measuring the reduced enzymatic activity of the beta-glucosidase together with genetic confirmation. Since numerous different mutations may be the cause of a particular lysosomal storage disease the sequencing of the entire beta-glucosidase gene is applied in Gaucher's disease in order to confirm the genetic diagnosis (Zimran, 2011). Although there are attempts to apply easy diagnostic methods based on associated biochemical abnormalities such as high alkaline phosphatase, angiotensin-converting enzyme (ACE) and immunoglobulin levels, or, in case of Gaucher's disease, by cell analysis showing "crinkled paper" cytoplasm and glycolipid-laden macrophages, there is an unmet need for a simple biochemical test exhibiting highly specific and highly sensitive detection at an early stage, monitoring progression of the disease and early monitoring the efficacy of applied therapies.

A biomarker should be technically feasible in many hands, easy to measure; useful, with a consistent, relative magnitude between patients and controls, or treated and untreated patients; reliable, precise, and accurate clinically, and classifiable as strongly predictive or prognostic. In GD some lysosomal enzymes, used as indirect biomarkers, were found to be elevated, including tartrate-resistant acid phosphatase, hexosaminidase, and a human chitinase, chitotriosidase. Thus, there are attempts to monitor the reduction of storage cells in tissues by measurement of such surrogate markers of Gaucher cells like chitotriosidase and CCL18 (Hollak et al., 1994; Boot et al., 2004). However, the use of plasma chitotriosidase as a Gaucher cell marker is hampered by the fact that patients, including those with Gaucher's disease, may be deficient in chitotriosidase activity due to a 24-base pair (bp) duplication in the chitotriosidase gene. Obviously these individuals cannot be monitored by the measurement of plasma chitotriosidase activity. The frequency of the homozygous 24-bp duplication in the chitotriosidase gene depends on the ethnicity and can vary between 6% and nearly 35% in the Latino population (unpublished data). In these cases the marker CCL18 is used. Furthermore, elevated levels of CCL18 were also found to be associated with a variety of diseases, such as different types of cancer and inflammation of joints, lungs and skin. For example, the ascitic fluid of patients suffering from ovarian cancer contains a significantly elevated level of CCL18 compared to patients without this carcinoma (Budd-Chiari syndrome). Since it attracts and activates specific immune cells CCL18 plays a role in tumor suppression. Furthermore, children having acute lymphocytic leukemia are found to exhibit elevated levels of CCL18. Plasma CCL18 levels do not reflect one particular clinical symptom, but rather are a reflection of the total body burden of Gaucher cells. The use of primary storage molecules as biomarker was assessed for glucosylceramide (Gb1) in plasma of Gaucher's disease patients and compared to the level of Gb1 in healthy individuals (Groener et al. 2008). Already in 1989 Rosengren et al. (1989) showed that in lipidoses not only the catabolism of the major sphingolipid but also its deacylated compound is affected. It is important to note that until today no use of a highly specific and highly sensitive biomarker is routinely used beside the methods described above, that exhibits an unsatisfactory limit of detection, sensitivity and/or specificity and thus proved to be unsuitable for clinical application

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Study Type : Observational
Estimated Enrollment : 250 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Lyso-Gb1 as Long-term Prognostic Biomarker in Gaucher Disease - an International Multicenter Epidemiological Study (LYSO-PROVE) to Determine the Prognostic Value of Lyso-Gb1 for Monitoring the Progress of Gaucher Disease
Study Start Date : March 2015
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : May 2022

Patients with genetically confirmed diagnosis of Gaucher disease type 1 without treatment prior to enrollment

Primary Outcome Measures :
  1. To demonstrate the correlation and predictive value of lyso-Gb1 concentration with the clinical severity of naïve, initially non-ERT/SRT Gaucher disease type 1 and during the study ERT/SRT-newly started Gaucher type 1 patients [ Time Frame: 48 month ]

Secondary Outcome Measures :
  1. To correlate lyso-Gb1 concentration with the clinical improvement of ERT or SRT treated Gaucher type 1 and the clinical course of non-treated patients based on GD-DS3,Quality of life measured with the SF-36 [ Time Frame: 48 month ]

Biospecimen Retention:   Samples With DNA
lyso-Gb1 as biomarker for Gaucher Disease For the purpose of measuring lyso-Gb1 one filter card is sent to the following laboratory, Centogene AG, Schillingallee 68, 18057 Rostock, Germany

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
male or female patients aged 6 months or older with genetically confirmed diagnosis of Gaucher disease type 1 without treatment prior to enrollment or no treatment for more than 24 months ago

Inclusion Criteria:

  • Male or female patients aged 6 months or older
  • Patients with genetically confirmed diagnosis of Gaucher disease type 1
  • No prior treatment with enzyme replacement therapy or substrate reduction therapy ro no traetment for more than 24 months
  • Signed informed consent by parents/legal guardian and patient

Exclusion Criteria:

  • Male or female patients being younger than 6 months
  • Patients without genetically confirmed diagnosis of Gaucher disease type 1
  • Gaucher disease 2 or 3
  • Patient is currently undergoing enzyme replacement therapy or substrate reduction therapy
  • Missing signed informed consent

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02416661

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Contact: Volha Skrahina, Dr +4938180113594 ext 594

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Pediatric department Debaghine's Hospital Universitary Hospital Center of Bab-El-Oued Recruiting
Algiers, Algeria, 16030
Contact: Souhila Melzi, MD         
Hôpital de Ben Aknoun BOUKHROUFA Abdelkader Service Rhumatologie Recruiting
Algiers, Algeria, 16306
Contact: Fadia Rahal, MD         
Universitary Hosspital Center,Bab-El-Oued Recruiting
Algiers, Algeria
Contact: Djennette Hakem, Prof.         
Contact: Abdelkrim Berrah, Prof.         
Pediatric practice Recruiting
Oran, Algeria, 31000
Contact: Houaria Cheriet, MD         
Principal Investigator: Houaria Cheriet, MD         
Service medicine interne EPH Bouguera Boulares Bekkaria Recruiting
Tébessa, Algeria, 12130
Contact: Souhlia Moundher, MD         
Gene Lab Recruiting
Cairo, Egypt
Contact: Ekram Fateen, Prof.         
Klinikum rechts der Isar der TU Recruiting
München, Germany
Contact: Claudia Regenbogen, Dr.         
Amrita Institute of Medical Sciences and Research Centre Recruiting
Cochin, India
Contact: Sheela Nampoothiri, Prof.         
Rainbow Children Hospital Recruiting
Hyderabad, India, 500034
Contact: Radha Rama Devi, MD         
Iran, Islamic Republic of
Sarem Women Hospital - Metabolic and Genetics Department Recruiting
Tehran, Iran, Islamic Republic of
Contact: Zahra Hadipour, MD         
Contact: Fatemeh Hadipou, MD         
Emek Medical Center Recruiting
Afula, Israel
Contact: Efrat Shalev, Dr.         
Shaare Zedek Medical Center Recruiting
Jerusalem, Israel, 93722
Contact: Ari Zimran, MD         
Contact: Tama Dinur, MD         
Principal Investigator: Ari Zimran, MD         
División de Genética Not yet recruiting
Guadalajara, Mexico, 44340
Contact: José Elias García-Ortiz, MD         
Children hospital's Rabat Recruiting
Rabat, Morocco, 10100
Contact: Nezha Mouane, Prof.         
Contact: Yamna Kriouile, Prof.         
Hopital d'Enfant Recruiting
Rabat, Morocco
Contact: Yamna Kriouile, Prof         
The Children's Hospital and the Institute of Child Health Recruiting
Lahore, Pakistan
Contact: Huma Cheema, Prof.         
Russian Federation
National Research Center for Hematology Recruiting
Moscow, Russian Federation, 125167
Contact: Elena Lukina, Prof.         
Contact: Kira Lukina, MD         
FETEEG Recruiting
Zaragoza, Spain
Contact: Pilar Giraldo, Dr         
Karolinska University, Hospital Huddinge, Hematology Center Not yet recruiting
Stockholm, Sweden, 141 86
Contact: Maciej Machaczka, Prof.         
Hospital Hedi Chaker Recruiting
Sfax, Tunisia, 1008
Contact: Hadji Mseddi Sondes         
Av. Pateón, Centro Clínico Profesional Caracas Not yet recruiting
Caracas, Venezuela
Contact: Liliana Vera, Prof.         
Sponsors and Collaborators
Centogene AG Rostock
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Principal Investigator: Arndt Rolfs, Prof Centogene AG Rostock

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Centogene AG Rostock Identifier: NCT02416661     History of Changes
Other Study ID Numbers: LP 06-2018
First Posted: April 15, 2015    Key Record Dates
Last Update Posted: April 30, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Keywords provided by Centogene AG Rostock:
Gaucher Disease type 1
Lymphatic Diseases
Lipid Metabolism, Inborn Errors
Lipid Metabolism Disorders
Additional relevant MeSH terms:
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Gaucher Disease
Lysosomal Storage Diseases
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
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Lipid Metabolism Disorders