Bezafibrate Trial in CPT2 Deficiency

Brief Title

Bezafibrate Trial in CPT2 Deficiency

Official Title

Clinical Trial on the Effect of Bezafibrate in the Muscular Form of Carnitine Palmitoyltransferase 2 Deficiency

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, 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).

Study Phase

Phase 3

Study Type


Primary Outcome

Rate of 3H-palmitate oxidation in the patients'lymphocytes and skeletal muscle

Secondary Outcome

 Rate of CPT2 enzymatic activity in the patients'lymphocytes and skeletal muscle


Carnitine Palmitoyl Transferase 2 Deficiency


bezafibrate (drug)


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

June 2006

Completion Date

July 2007

Eligibility Criteria

        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

          -  treatment with another hypolipidemic drug ("statins) or with anticoagulant

          -  pregnancy or lactation during the period of fibrate therapy




18 Years - N/A

Accepts Healthy Volunteers



Bruno EYMARD, M.D, 144495647, [email protected]

Location Countries


Location Countries


Administrative Informations



Organization ID


Study Sponsor

Assistance Publique - Hôpitaux de Paris


 Association Française contre les Myopathies (AFM), Paris

Study Sponsor

Bruno EYMARD, M.D, Study Chair, Service de Neurologie 2 Groupe hospitalier Pitié-Salpétriere, Paris, France

Verification Date

April 2007