Ignite Creation Date:
2024-05-05 @ 4:52 PM
Last Modification Date:
2024-10-26 @ 9:25 AM
Study NCT ID:
NCT00336167
Status:
UNKNOWN
Last Update Posted:
2007-04-09
First Post:
2006-06-09
Brief Title:
Bezafibrate Trial in CPT2 Deficiency
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Clinical Trial on the Effect of Bezafibrate in the Muscular Form of Carnitine Palmitoyltransferase 2 Deficiency
Status:
UNKNOWN
Status Verified Date:
2007-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of this study is to determine whether bezafibrate is effective in the treatment of the muscular adult form of carnitine palmitoyltransferase 2 deficiency
Detailed Description:
Fatty acids are the main source of energy for non-glucodependent tissues during fasting and prolonged exercise Carnitine Palmitoyltransferase CPT 1 and 2 are a key-enzymes in the regulation of mitochondrial FAO by governing entry of long-chain fatty acids within the mitochondrial matrix CPT2 deficiency is among the most common inherited disorders of mitochondrial fatty acid oxidation FAO The neonatal and infantile forms of CPT2 deficiency are life-threatening diseases with a hepatocardiomuscular presentation The adult form presents as recurrent attacks of rhabdomyolysis mostly triggered by prolonged exercise fasting and infections and is usually considered as a mild disease However patients commonly suffers permanent muscle weakness andor frequent weekly and sometimes daily attacks of rhabdomyolysis that occasionally result in severe episodes of acute renal insufficiency and rarely in sudden death
Difference in the clinical severity of the distinct forms of CPT2 deficiency correlates in some extent with in vitro data Thus when measured in fibroblasts or lymphocytes the residual CPT2 activity and the long-chain fatty acid oxidation LCFAO are usually less than 10 of control values in the neonatal and infantile forms while they most often are over 20 of controls in the adult form
Clinical management of CPT2-deficient patients remains poor and most often does not succeed in significantly improving their clinical condition Treatment mostly relies so far on restriction in lipid intake and limitation of fasting and exercise We decided a few years ago to set up a project of pharmacological therapy for this disease based upon in vitro testing of pharmacological agents potentially able to increase the residual enzymatic activity in CPT2-deficient cell lines Some of the best candidate drugs were PPAR agonists used since over two decades as hypolipidemic drugs PPAR alpha is a transcription factor belonging to the superfamily of steroid-thyroid nuclear receptors that has been shown to regulate the constitutive expression of the CPT2 gene and protein in the adult mouse heart and liver and to mediate up-regulation of the CPT2 gene in response to fibrates in mouse liver We recently shown that bezafibrate a PPAR alpha agonist was able to restore close to the normal the apparent CPT2 activity and the LCFAO in both fibroblasts and cultured myoblasts from several patients with the adult form of CPT2 deficiency Therefore the purpose of the current application is to test in vivo the potentially beneficial effect of bezafibrate therapy in a cohort of 12 patients with the adult form of this disease All patients are clinically managed by either of the 2 research groups involved in this project namely the Neurology department of lhospital Pitié-Salpétrière and the Genetics department of lhospital Necker-Enfants Malades Patients fulfilling inclusion criteria will first be submitted to a 6-month period of clinical and biological survey with a written registration of each clinical symptoms and measurement of CK activity once a month The initial examination will include i muscular testing ii measurement of CPT2 activity LCFAO and quantitation of CPT2 transcripts both in lymphocytes and in a fresh small sample of skeletal muscle and iiiassay of acylcarnitines a compound accumulated upstream of the metabolic block in blood Bezafibrate will thereafter be daily supplied as a 400 to 600 mg dose according to the renal function for 6 months Follow-up will focus on the muscular symptomatology and on the hepatic muscular and renal tolerance of the treatment At the end of the clinical trial each patient will be submitted to an examination similar to the initial one including a second muscle biopsy used for measurement of CPT2 activity LCFAO and amount of CPT2 transcripts It has to be emphasized that for the first time such a therapy should impact directly the cause of the disease the defective enzyme activity and not only its consequences accumulation of cell lipid and defective energy production
Difference in the clinical severity of the distinct forms of CPT2 deficiency correlates in some extent with in vitro data Thus when measured in fibroblasts or lymphocytes the residual CPT2 activity and the long-chain fatty acid oxidation LCFAO are usually less than 10 of control values in the neonatal and infantile forms while they most often are over 20 of controls in the adult form
Clinical management of CPT2-deficient patients remains poor and most often does not succeed in significantly improving their clinical condition Treatment mostly relies so far on restriction in lipid intake and limitation of fasting and exercise We decided a few years ago to set up a project of pharmacological therapy for this disease based upon in vitro testing of pharmacological agents potentially able to increase the residual enzymatic activity in CPT2-deficient cell lines Some of the best candidate drugs were PPAR agonists used since over two decades as hypolipidemic drugs PPAR alpha is a transcription factor belonging to the superfamily of steroid-thyroid nuclear receptors that has been shown to regulate the constitutive expression of the CPT2 gene and protein in the adult mouse heart and liver and to mediate up-regulation of the CPT2 gene in response to fibrates in mouse liver We recently shown that bezafibrate a PPAR alpha agonist was able to restore close to the normal the apparent CPT2 activity and the LCFAO in both fibroblasts and cultured myoblasts from several patients with the adult form of CPT2 deficiency Therefore the purpose of the current application is to test in vivo the potentially beneficial effect of bezafibrate therapy in a cohort of 12 patients with the adult form of this disease All patients are clinically managed by either of the 2 research groups involved in this project namely the Neurology department of lhospital Pitié-Salpétrière and the Genetics department of lhospital Necker-Enfants Malades Patients fulfilling inclusion criteria will first be submitted to a 6-month period of clinical and biological survey with a written registration of each clinical symptoms and measurement of CK activity once a month The initial examination will include i muscular testing ii measurement of CPT2 activity LCFAO and quantitation of CPT2 transcripts both in lymphocytes and in a fresh small sample of skeletal muscle and iiiassay of acylcarnitines a compound accumulated upstream of the metabolic block in blood Bezafibrate will thereafter be daily supplied as a 400 to 600 mg dose according to the renal function for 6 months Follow-up will focus on the muscular symptomatology and on the hepatic muscular and renal tolerance of the treatment At the end of the clinical trial each patient will be submitted to an examination similar to the initial one including a second muscle biopsy used for measurement of CPT2 activity LCFAO and amount of CPT2 transcripts It has to be emphasized that for the first time such a therapy should impact directly the cause of the disease the defective enzyme activity and not only its consequences accumulation of cell lipid and defective energy production
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None