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Bezafibrate Trial in CPT2 Deficiency

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. Read our disclaimer for details. Identifier: NCT00336167
Recruitment Status : Unknown
Verified April 2007 by Assistance Publique - Hôpitaux de Paris.
Recruitment status was:  Recruiting
First Posted : June 13, 2006
Last Update Posted : April 9, 2007
Association Française contre les Myopathies (AFM), Paris
Institut National de la Santé Et de la Recherche Médicale, France
Information provided by:
Assistance Publique - Hôpitaux de Paris

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

Condition or disease Intervention/treatment Phase
Carnitine Palmitoyl Transferase 2 Deficiency Drug: bezafibrate (drug) Phase 3

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, and/or 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 l'hospital Pitié-Salpétrière and the Genetics department of l'hospital 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 iii)assay 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).

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Study Type : Interventional  (Clinical Trial)
Enrollment : 12 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Trial on the Effect of Bezafibrate in the Muscular Form of Carnitine Palmitoyltransferase 2 Deficiency
Study Start Date : June 2006
Estimated Study Completion Date : July 2007

Primary Outcome Measures :
  1. Rate of 3H-palmitate oxidation in the patients'lymphocytes and skeletal muscle

Secondary Outcome Measures :
  1. Rate of CPT2 enzymatic activity in the patients'lymphocytes and skeletal muscle
  2. Rate of palmitoyl-L-carnitine oxidation in the patients' skeletal muscle
  3. Steady-state amount of CPT2 mRNA in the patients'skeletal muscle

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • occurrence of at least 5 attacks of rhabdomyolysis or of severe myalgias per year, AND/OR permanent muscle weakness objectivized by muscle testing outside a rhabdomyolysis attack AND
  • significant decrease in both the CPT2 activity and the rate of long-chain fatty acid oxidation measured in lymphocytes and/or in a skeletal muscle sample outside a rhabdomyolysis attack

Exclusion Criteria:

  • age below 18 years
  • less than 5 attacks of rhabdomyolysis or severe myalgias per year AND absence of muscle impairment detected by muscle testing
  • liver failure, renal failure, hyperhomocysteinemia prior to setting up the bezafibrate therapy
  • treatment with another hypolipidemic drug (“statins) or with anticoagulant
  • pregnancy or lactation during the period of fibrate therapy

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): NCT00336167

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Contact: Jean-Paul Bonnefont, M.D., Ph.D. 144495647 ext 0033
Contact: Jean Bastin, Ph D;

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Jean Paul Bonnefont Recruiting
Paris, France, 75015
Contact: Jean-Paul Bonnefont, MD; PhD   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Association Française contre les Myopathies (AFM), Paris
Institut National de la Santé Et de la Recherche Médicale, France
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Study Chair: Bruno EYMARD, M.D Service de Neurologie 2 Groupe hospitalier Pitié-Salpétriere, Paris, France
Principal Investigator: Jean Paul BONNEFONT, M.D., Ph D, Unite INSERM U781

Layout table for additonal information Identifier: NCT00336167     History of Changes
Other Study ID Numbers: 05-05-19
First Posted: June 13, 2006    Key Record Dates
Last Update Posted: April 9, 2007
Last Verified: April 2007
Keywords provided by Assistance Publique - Hôpitaux de Paris:
carnitine palmitoyl transferase 2 deficiency
Fatty acid oxidation
Additional relevant MeSH terms:
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Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Hypolipidemic Agents
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents