Bezafibrate Trial in CPT2 Deficiency
Information source: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Carnitine Palmitoyl Transferase 2 Deficiency
Intervention: bezafibrate (drug) (Drug)
Phase: Phase 3
Status: Recruiting
Sponsored by: Assistance Publique - Hôpitaux de Paris Official(s) and/or principal investigator(s): Bruno EYMARD, M.D, Study Chair, Affiliation: Service de Neurologie 2 Groupe hospitalier Pitié-Salpétriere, Paris, France Jean Paul BONNEFONT, M.D., Ph D,, Principal Investigator, Affiliation: Unite INSERM U781
Overall contact: Jean-Paul Bonnefont, M.D., Ph.D., Phone: 144495647, Ext: 0033, Email: bonnefon@necker.fr
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
Clinical Details
Official title: Clinical Trial on the Effect of Bezafibrate in the Muscular Form of Carnitine Palmitoyltransferase 2 Deficiency
Study design: Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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 muscleRate of palmitoyl-L-carnitine oxidation in the patients' skeletal muscle Steady-state amount of CPT2 mRNA in the patients'skeletal muscle
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).
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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 therapy
- treatment with another hypolipidemic drug (“statins) or with anticoagulant
- pregnancy or lactation during the period of fibrate therapy
Locations and Contacts
Jean-Paul Bonnefont, M.D., Ph.D., Phone: 144495647, Ext: 0033, Email: bonnefon@necker.fr
Jean Paul Bonnefont, Paris 75015, France; Recruiting Jean-Paul Bonnefont, MD; PhD, Email: bonnefont@necker.fr
Additional Information
Starting date: June 2006
Last updated: April 6, 2007
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